Accepted Manuscript Title: PHOTODYNAMIC THERAPY IN THE TREATMENT OF BRAIN TUMOURS. A FEASIBILITY STUDY Author: Vicente Vanaclocha Manuel Sureda Ignacio Azinovic Joseba Rebollo Rosa Ca˜no´ n Nieves Saiz Sapena Francisco Garc´ıa Cases Antonio Brugarolas PII: DOI: Reference:
S1572-1000(15)00069-1 http://dx.doi.org/doi:10.1016/j.pdpdt.2015.05.007 PDPDT 656
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
29-12-2014 7-5-2015 18-5-2015
Please cite this article as: Vanaclocha V, Sureda M, Azinovic I, Rebollo J, Ca˜no´ n R, Sapena NS, Cases FG, Brugarolas A, PHOTODYNAMIC THERAPY IN THE TREATMENT OF BRAIN TUMOURS. A FEASIBILITY STUDY, Photodiagnosis and Photodynamic Therapy (2015), http://dx.doi.org/10.1016/j.pdpdt.2015.05.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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PDT is a local treatment modality without long-term systemic effects.
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Chemo and RT continue to present important limitations in brain tumors
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41 patients with a median age of 49, with primary brain tumors were treated with PDT
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Results are not inferior to those in literature, in spite of the characteristics of the patients
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PDT can be considered as an adjunctive to other modalities in brain tumors
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PHOTODYNAMIC THERAPY IN THE TREATMENT OF BRAIN TUMOURS. A
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FEASIBILITY STUDY.
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Vicente Vanaclocha1, Manuel Sureda2, Ignacio Azinovic2, Joseba Rebollo2, Rosa Cañón2,
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Nieves Saiz Sapena1, Francisco García Cases2, Antonio Brugarolas2
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Torrevieja, Torrevieja, Alicante, Spain
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Hospital 9 de Octubre, Valencia, Spain 2Plataforma de Oncología-Hospital Quirón
Corresponding Author: Manuel Sureda, MD, PhD
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Plataforma de Oncología-Hospital Quirón Torrevieja,
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c/Partida de la Loma s/n
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03184 Torrevieja, Alicante, Spain
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Tel +34651848837
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[email protected]
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Background
Photodynamic therapy (PDT) constitutes a treatment modality that combines a photosensitizing agent with exposure to laser light in order to elicit phototoxic reactions that selectively destroy tumor cells and spare normal cells. PDT is a local treatment modality without long-term systemic effects. Its application can be repeated more than once to the same area without accumulative effects.
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Methods
Patients diagnosed with primary brain tumors were treated with PDT. Treatment consisted in administration of the photosensitizer followed by craniotomy, surgical resection and laser illumination of the surgical bed. Primary brain tumors received also temozolomide-based chemotherapy and radiotherapy (RT). Results
From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of 49 years (range 13 to 70) diagnosed of primary brain tumors were included in the study. In 7 patients PDT was repeated at the time of the relapse. In 22 episodes PDT was part of the initial treatment of primary brain tumors and in 26 episodes was part of the treatment at relapse.
Median PFS observed was 10 months for GBM (95% confidence interval 5.7-14.3), 26 months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS was 9 months for GBM (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50 months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is due to patients not censored for PFS because they die from causes other than tumor progression. Median OS since first diagnosis was 17 months for GBM (95% CI 15.2-17.8), 66 months for AA (95% CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8). Side effects were mild and manageable. Conclusions
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This study confirms that PDT can be considered as an adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors, excluding those patients with thalamic or brain stem locations. It adds therapeutic effect without adding significant toxicity. In order to improve its contribution, it is essential to find new drugs with more penetration in order to destroy tumor cells more deeply at resection margins.
51 Keywords: photodymamic therapy; brain tumors; neurosurgery
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All the authors above mentioned declare that there are no conflicts of interest
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INTRODUCTION
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Gliomas account for approximately 40~50% of all intracranial malignancies. The prognosis
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of patients with malignant glioma is dismal, especially those harboring a glioblastoma
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(GBM), with a median survival of less than 2 years after the initial diagnosis1, 2. Over the
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years and despite all attempts to improve the outcome with surgery, radiotherapy and
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chemotherapy, there has been only very little improvement. Thus new treatment modalities
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are needed.
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Survival of patients suffering from malignant brain tumors is highly dependent on the
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extent of surgical resection, but the completeness of tumor resection has to be maximized
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without affecting critical brain structure and function. As most recurrences occur within 2
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cm of the original tumor site1, more aggressive local therapies are necessary to eradicate
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tumor cells that invade adjacent normal brain tissue. Standard postoperative treatment is a
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combination of radio and chemotherapy including temozolomide2, 3.
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Photodynamic therapy (PDT) constitutes a treatment modality that combines a
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photosensitizing agent with exposure to laser light in order to elicit phototoxic reactions
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that selectively destroy tumor cells and spare normal cells4.
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PDT involves the administration of a photosensitizer and the illumination of the target with
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light of a wavelength corresponding to the absorption peak of the administered drug. The
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absorption of photon energy by the sensitizer induces a photochemical reaction that results
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in cellular damage leading to cell death4. Cancer cells retain more photosensitizer inside
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them than surrounding normal cells after a specified amount of time has passed, causing a
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relative selectivity regarding this treatment5. Additional advantages of PDT are that it can
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induce apoptosis in cancer cells, with no effects in the extra-cellular matrix that remains
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forming a scaffold for the surrounding normal tissue to advance over and it has vascular
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mediated effects that contribute to tumor control4-6.
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PDT is a local treatment modality. Its application can be repeated more than once to the
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same area without accumulative effects7, 8. It does not negatively affect other treatment
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modalities, such as radiation or chemotherapy, leaving further treatment options open.
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All the characteristics described, in addition to the initial favorable experiences
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communicated by other groups4, 5, prompted us to perform a feasibility study of PDT in
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brain tumors. Initially porfimer sodium (Photofrin™, Pinnacle Biologics, Bannockburn IL,
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USA) was chosen4, 5. When second-generation photosensitizers were ready to use, we
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switched to temoporfin (meta-tetrahydroxyphenylchlorin –mTHPC-, Foscan™ Biolitec,
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Jena, Germany)9-11. mTHPC has a deeper penetration in brain tissue and it is cleared from
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the skin much faster than porfimer sodium.
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PATIENTS AND METHODS
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Study Subjects
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Patients diagnosed with primary brain tumors and neither contraindications for general
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anesthesia nor brain surgery were included. After death of two patients with thalamic
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Study was reviewed and approved by the Hospital Ethics Committee. Written informed
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consent and Compassionate Use approval from Spanish Health Ministry were obtained for
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each patient according to Spanish regulation.
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PDT Therapy
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Forty eight hours before the surgical procedure, porfimer sodium was administered at a
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dose of 2 mg/kg body weight, through an intravenous drip line. The infusion lasted over 30
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minutes. Photoactivation of porfimer was obtained during surgery by exposure of the
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residual cavity to a non-thermal light at a wavelength of 630 nm, provided by a Ceralas
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PDT 630 Diode Laser (CeramOptec GmbH, Bonn, Germany). The light dose administered
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in this study was 75 J/cm2.
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mTHPC was administered 96 hours before surgery, at 0.15 mg/kg body weight, into a thick
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vein of the arm for 6 minutes. Photoactivation of mTHPC was obtained during surgery by
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exposure of the surgical cavity to a non-thermal light at a wavelength of 652 nm provided
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by a laser Ceralas PDT 652 (CeramOptec, Bonn, Germany). The light dose administered
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was 20 J/cm2.
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Usually post-excision cavities vary in size and are irregular in shape. The Neurosurgeon
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calculates the amount of light to be delivered to the treatment site with the assistance of
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both Radiotherapy and Medical Physics specialists. Two optical fibers were used, alone or
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in combination: one designed to produce an uniform circular field, suitable for illumination
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of flat surfaces and one diffuser fiber for obtaining a spherical field. Personalized fields
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were calculated for every patient with the aim of avoiding dark zones and overdosed ones.
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Once in place, the fibers were maintained in the adequate position by means of a
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mechanical arm.
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According to the protocol and the recommendations of the manufacturers, an illustrated
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booklet explaining detailed written guidelines for light exposure was provided to the
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patient, families and referring physicians, making them fully aware about the importance of
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complying with the light exposure requirements in PDT.
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Surgical procedure
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All pre-operative studies were performed before administering the photosensitizing agent.
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The surgical procedure took place 48 hours after porfimer sodium administration and 96
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hours after mTHPC administration, respectively.
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Craniotomy with radical tumor resection under microscopic guidance was performed. Once
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the surgical removal of the tumor was finished, a laser light was applied to the tumor bed to
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destroy the remaining tumor cells invading the normal looking brain tissue. Light was
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delivered with a laser at 630 nm, 75 J/cm2 in porfimer sodium patients and at 652 nm, 20
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J/cm2 in the mTHPC ones. While the laser light was applied the surgical cavity was cooled
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with a continuous infusion of Intralipid™ (Fresenius Kabi, Barcelona, Spain) at a
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concentration of 2%, diluted in saline serum. Standard procedures for safe laser use were
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strictly followed. In the operating room no direct light was used and the areas of the patient
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not exposed in the surgical procedure were covered with thick blankets. In the surgical
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field, the non-tumor areas were covered with moist gauzes. Afterwards the wound was
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closed in the usual manner. Once in the ICU, patients were kept in a special room with no
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natural sunlight.
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Post-surgery procedure
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Patients left the hospital usually 5-7 days post-op, at night, after sunset. Once at home,
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sunlight was avoided until 4 weeks (porfimer sodium) or 2 weeks (mTHPC) had elapsed
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since the administration of the photosensitizing agent. Patients’ individual sensitivity to
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light was tested. In any case patients were instructed to observe precautions to avoid intense
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sunlight exposure for the first 7 days.
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Post-operatively, patients received temozolomide (TMZ)-based chemotherapy and
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radiotherapy (RT, 60 Gy) according to Stupp protocol2, 3. In case of progression to previous
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TMZ and/or RT, they received intraarterial cis-platinum and bevacizumab. Radiosurgery
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was considered for small recurrences.
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Patients were evaluated with physical examination, blood test including hemogram and
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basic biochemistry and MRI at 1 and 3 months and then at 3 months interval until relapse
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or death.
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Statistical analysis
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Data are reported as means and 95% confidence interval (CI). All statistical tests were
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performed using the SPSS 17.0 software (SPSS, Chicago, IL, USA). The survival data were
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analyzed by Kaplan-Meier method.
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RESULTS
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From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of
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49 years (range 13 to 70) diagnosed of primary brain tumors were treated with PDT.
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Histologies were GBM (n=20), anaplastic astrocytoma (AA, n=10), low grade astrocytoma
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(LGG, n=4), oligodendroglioma (OD, n=7, 4 anaplastic). In 7 patients PDT was repeated at
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the time of the relapse, and for the purpose of analysis of progression-free survival (PFS)
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and overall survival (OS) they have been considered as separate procedures. In 22 episodes
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PDT was part of the initial treatment and in 26 episodes was part of the treatment at relapse.
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Therapy side effects
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Two patients with thalamic tumors treated at the initial phase of the study died in early
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post-op period. A 40-y old male diagnosed with GBM of left thalamic region received PTD
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with Photofrin after a complete resection. He presented massive edema at the end of the
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procedure, refractory to aggressive antiedema measures. The other, a 40-y old male
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diagnosed with AA of the left thalamic region, was operated, leaving a plaque of residual
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tumor close to the internal capsule. He received PTD with Photofrin. Two days later he
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presented massive and refractory edema. We decided to add thalamic or brain stem location
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as absolute exclusion criteria. Otherwise, no other cases of massive edema were observed.
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Mild postoperative brain edema was adequately controlled with corticosteroid treatment.
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Neurologic post-operative deficits occurred in 5 patients (4 hemiparesia, 1 hydrocephalus, 1
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ptosis). Three patients with hemiparesia recovered in 3 to 17 days with dexametasone and
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mannitol; the fourth continues alive but with residual right hemiparesia, 23 months after
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surgery. The hydrocephalus required surgical correction with brain-abdominal derivation.
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Most patients complained of moderate pain in the operated area in the first days after
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treatment, which could be adequately managed with common analgesics.
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One scalp burn requiring plastic surgery with cutaneous graft was observed. Other
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cutaneous toxicities were one case of blisters on the forearm and other of erythema in
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forearm, caused by a negligent observation of specific protective measures about light
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exposure. A case of burn on the thumb fingernail was also observed, induced by the
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pulsoxymeter in ICU. Since then, the pulsoxymeter was changed of finger every hour and
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not used when the patient was fully awake. Slight dermatitis along the course of the vein
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used for the injection of the photosensitizer was almost universally observed. Dermatologic
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complications were usually well managed with conservative treatment and resolved without
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sequealae.
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Survival
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Median PFS observed was 10 months for GBM (95% confidence interval 5.7-14.3), 26
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months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS
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was 9 months for GBM (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50
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months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is
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due to 1 patient with GBM and 2 with AA not censored for PFS because they die from
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causes other than tumor progression (1 pneumonia, 1 cardiomiopathy, 1 sepsis). Median OS
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since first diagnosis was 17 months for GBM (95% CI 15.2-17.8), 66 months for AA (95%
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CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8) (see Figure 1).
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Four patients are alive at the moment without evidence of active disease: one patient with
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OD, treated with porfimer sodium at the third relapse and with mTHPC at the fourth relapse
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(238 months since initial diagnosis), one with LGG treated with porfimer sodium in the
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initial surgery (152 months since first diagnosis), one with OD, treated with mTHPC at the
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third relapse after two previous surgeries (142 months since initial diagnosis), and the last
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one with LGG, treated with porfimer sodium in the initial surgery and with mTHPC at
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relapse (132 months since first diagnosis).
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In several cases of high grade glioma a particular pattern of progression was observed. It
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consisted in tumor growth in points of the surgical bed where a non-optimal exposure to the
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laser light was suspected considering its irregular shape as well as recurrence beyond the
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edges of the surgical cavity and/or distant recurrence including the contralateral
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hemisphere.
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In 22 episodes PDT was part of initial treatment of primary brain tumors and in 26 episodes
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was part of the treatment at relapse. Twenty one procedures were performed using porfimer
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sodium and 27 using mTHPC. Comparisons in efficacy between photosensitizers have not
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been possible due to the heterogeneity of the series and the small number of patients in each
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group to draw definitive conclusions.
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DISCUSION
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Local invasion is characteristic of glioma growth and the most frequent cause of recurrence.
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Around 90% of recurrences diagnosed after initial surgery are localized in a 2-cm area
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surrounding the primary tumor bed1,
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critical for the prevention of glioma recurrence.
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Adjuvant RT, alone or in combination with chemotherapy, has been administered after
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surgery with the aim of killing any tumor cell infiltrating normal brain. Multiple trials with
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different agents and schedules were published with no clear benefit. In 2005, Stupp and
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cols. reported the final results of a randomized trial, showing that the addition of TMZ to
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RT as initial adjuvant treatment prolonged survival of patients with GBM. Five hundred
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seventy-three patients were randomly assigned to either standard RT alone or RT and
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concomitant and maintenance administration of TMZ (TMZ/RT). Patients treated with
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TMZ/RT had a median survival time of 15 months, compared with 12 months for the
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patients initially treated with RT alone. The 2-year survival rate was 26% for the TMZ/RT
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group compared with only 10% in the RT group2, 3.
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Despite these encouraging results, chemo and RT continue to present important limitations.
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RT induces damage and long term effects on the normal brain tissue, a tribute frequently
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paid in the attempt to control tumor growth. New modalities as image modulated RT
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(IMRT) or 3D conformation permit a more selective radiation delivery to the critical areas.
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In selected patients, a second irradiation is feasible, but still far from a dose that could be
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considered curative.
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. Therefore, removal of residual cancer cells is
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Some encouraging results were published with high dose chemotherapy in the context of
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multidisciplinary programs and selected patients, but, in general, no significant advances in
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chemotherapy of gliomas have been reported after TMZ13.
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The study AVAglio has demonstrated an improvement in PFS without significant changes
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in OS with bevacizumab, an antiangiogenic drug. It has shown also an improvement in
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quality of life reflected in higher time to neurological deterioration and low corticoids
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consumption in comparison with non-bevacizumab treated patients. On the other hand,
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antiangiogenics interfere with the normal healing of the surgical wounds. Definitive role of
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bevacizumab in gliomas has to be defined14.
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In any case, the current survival rates for malignant brain gliomas treated with surgery,
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radio and chemotherapy has not significantly changed over the years, showing that more
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effective treatment strategies need to be explored.
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Use of 5-amino-delta-levulinic acid or other photoactive agents has been postulated for
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increasing the radicality of the surgical removal, helping to detect residual tumor by its
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luminescence, otherwise not observed by the naked eye7,
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radical removal is not always possible in the brain as the surgical excision of small amount
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of tissue in relevant brain areas can result in significant morbidity.
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PDT has been applied with great success in many areas of medicine. Its first application to
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brain tumors dates back to the 1988 Kaye's team series17. This group treated 56 brain tumor
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cases with a mixed pathology and saw no increase in permanent neurological deficits with
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no technical complexity and with a promising increase in the survival rate. They later
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updated their series confirming initial observations18, 19. Other reports from Canada20 and
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those from Eljamel et al.8, 21-23 in recent years have not only reproduced initial results but
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also have explored modifications in technique in an attempt to improve final results. New
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promising porfirin derivatives are being currently evaluated for clinical use24.
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Data from this study confirm the feasibility of adding PDT to the standard therapy of
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malignant brain tumors. The results found in this series are not inferior to those found in
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literature, in spite of the particular characteristics of the patients. Nineteen of the 41 patients
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were treated at relapse, after one or more surgeries and chemo/RT. The number of patients
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operated with recurrences makes this series more valuable.
8, 15, 16
.Unfortunately such a
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Some LGG can be controlled with standard treatment. Nevertheless, the pre-op diagnosis of
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a LGG is frequently based in stereotactic biopsies and/or radiologic findings, and it has to
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be remarked that an unequivocal diagnosis is obtained only after tumor removal when the
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anatomical location permits it. Mixed tumors, unusual radiologic findings and relapses are
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not uncommon and these were the reasons for including LGG in the study25.
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Local control of the disease has been satisfactory, particularly in LGG. Recurrences in
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GBM often happened at distant sites from the PDT treated surgical bed. In some cases,
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including two of the patients alive at this moment, longer survivals were obtained after re-
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operation with PDT, suggesting that PDT can be repeated with no accumulative effects.
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In young patients the possibility of treating the tumor without RT is particularly useful,
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since it avoids the potential for radiation-induced tumors later in life, and prevents the long-
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term sequelae after RT. That is the case of one of our patients treated when he was 13 years
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old for a recurrent OD. In spite of not receiving RT is still free of recurrence eight years
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later.
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Both reported deaths were due to strong post-op edema in thalamic region. Patients with
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thalamic and brain stem tumors should be discarded for PDT until more effective methods
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for controlling immediate post-op edema are available.
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mTHPC infusion-related local pain has been repeatedly reported6. In our series we found
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essential that the intravenous injection be carried out slowly (the manufacturer's
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recommendation is over 6 minutes) and in a thick caliber vein of the forearm.
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Photosensitivity skin reactions are avoidable. Minor skin photosensitivity reactions due to
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exposure to natural sunlight might be completely avoided by strict compliance of the light
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exposure recommendations. In our series, none was of clinical relevance except for the
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scalp burn requiring plastic surgery. There are other concerns such as photosensitizer
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extravasation while being injected and subungual burn due to pulse oxymeter, that need
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careful attention of the caring team to avoid them.
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Slight dermatitis along the course of the vein used for the injection of the photosensitizer
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was almost universally observed. The most probable origin is microextravasation, causing
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retention of the drug in perivascular area.
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Although the present and some previous PDT studies are based on a relatively small
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number of patients and in inhomogeneous samples, they suggest an encouraging benefit for
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patients with brain tumors. This study confirms that PDT can be considered as an
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adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors,
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excluding those patients with thalamic or brain stem locations.
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Photodiagn Photodyn Ther 2005; 1: 303- 310.
23. Moseley H, McLean C, Hockaday S, Eljamel S. In vitro light distributions from intracranial PDT balloons. Photodiag Photodyn Ther 2007;4:213- 220.
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22. Eljamel MS. Brain PDD and PDT unlocking the mystery of malignant gliomas.
24. Hiramatsu R, Kawabata S, Miyatake SI et al. Application of a novel boronated
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porphyrin (H2OCP) as a dual sensitizer for both PDT and BNCT. Lasers Surg Med
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2011;43:52-58.
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25. Grier JT, Batchelor T. Low-grade gliomas in adults. The Oncologist 2006;11:681-693.
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Kaplan Meier curves corresponding to PFS, OS and OS since diagnosis, for GBM (••••), AA (•−•−•), OD
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Picture 1. A general view of the surgical theater during the PTD procedure
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Picture 2. A detail of the surgical bed during illumination phase, showing cooling with Intralipid solution
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Picture 3. Register formulary for the procedure parameters
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S1572-1000(15)00069-1 http://dx.doi.org/doi:10.1016/j.pdpdt.2015.05.007 PDPDT 656
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
29-12-2014 7-5-2015 18-5-2015
Please cite this article as: Vanaclocha V, Sureda M, Azinovic I, Rebollo J, Ca˜no´ n R, Sapena NS, Cases FG, Brugarolas A, PHOTODYNAMIC THERAPY IN THE TREATMENT OF BRAIN TUMOURS. A FEASIBILITY STUDY, Photodiagnosis and Photodynamic Therapy (2015), http://dx.doi.org/10.1016/j.pdpdt.2015.05.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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PDT is a local treatment modality without long-term systemic effects.
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Chemo and RT continue to present important limitations in brain tumors
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41 patients with a median age of 49, with primary brain tumors were treated with PDT
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Results are not inferior to those in literature, in spite of the characteristics of the patients
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PDT can be considered as an adjunctive to other modalities in brain tumors
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PHOTODYNAMIC THERAPY IN THE TREATMENT OF BRAIN TUMOURS. A
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FEASIBILITY STUDY.
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Vicente Vanaclocha1, Manuel Sureda2, Ignacio Azinovic2, Joseba Rebollo2, Rosa Cañón2,
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Nieves Saiz Sapena1, Francisco García Cases2, Antonio Brugarolas2
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Torrevieja, Torrevieja, Alicante, Spain
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Hospital 9 de Octubre, Valencia, Spain 2Plataforma de Oncología-Hospital Quirón
Corresponding Author: Manuel Sureda, MD, PhD
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Plataforma de Oncología-Hospital Quirón Torrevieja,
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c/Partida de la Loma s/n
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03184 Torrevieja, Alicante, Spain
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Tel +34651848837
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[email protected]
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Background
Photodynamic therapy (PDT) constitutes a treatment modality that combines a photosensitizing agent with exposure to laser light in order to elicit phototoxic reactions that selectively destroy tumor cells and spare normal cells. PDT is a local treatment modality without long-term systemic effects. Its application can be repeated more than once to the same area without accumulative effects.
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Methods
Patients diagnosed with primary brain tumors were treated with PDT. Treatment consisted in administration of the photosensitizer followed by craniotomy, surgical resection and laser illumination of the surgical bed. Primary brain tumors received also temozolomide-based chemotherapy and radiotherapy (RT). Results
From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of 49 years (range 13 to 70) diagnosed of primary brain tumors were included in the study. In 7 patients PDT was repeated at the time of the relapse. In 22 episodes PDT was part of the initial treatment of primary brain tumors and in 26 episodes was part of the treatment at relapse.
Median PFS observed was 10 months for GBM (95% confidence interval 5.7-14.3), 26 months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS was 9 months for GBM (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50 months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is due to patients not censored for PFS because they die from causes other than tumor progression. Median OS since first diagnosis was 17 months for GBM (95% CI 15.2-17.8), 66 months for AA (95% CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8). Side effects were mild and manageable. Conclusions
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This study confirms that PDT can be considered as an adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors, excluding those patients with thalamic or brain stem locations. It adds therapeutic effect without adding significant toxicity. In order to improve its contribution, it is essential to find new drugs with more penetration in order to destroy tumor cells more deeply at resection margins.
51 Keywords: photodymamic therapy; brain tumors; neurosurgery
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INTRODUCTION
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Gliomas account for approximately 40~50% of all intracranial malignancies. The prognosis
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of patients with malignant glioma is dismal, especially those harboring a glioblastoma
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(GBM), with a median survival of less than 2 years after the initial diagnosis1, 2. Over the
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years and despite all attempts to improve the outcome with surgery, radiotherapy and
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chemotherapy, there has been only very little improvement. Thus new treatment modalities
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are needed.
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Survival of patients suffering from malignant brain tumors is highly dependent on the
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extent of surgical resection, but the completeness of tumor resection has to be maximized
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without affecting critical brain structure and function. As most recurrences occur within 2
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cm of the original tumor site1, more aggressive local therapies are necessary to eradicate
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tumor cells that invade adjacent normal brain tissue. Standard postoperative treatment is a
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combination of radio and chemotherapy including temozolomide2, 3.
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Photodynamic therapy (PDT) constitutes a treatment modality that combines a
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photosensitizing agent with exposure to laser light in order to elicit phototoxic reactions
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that selectively destroy tumor cells and spare normal cells4.
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PDT involves the administration of a photosensitizer and the illumination of the target with
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light of a wavelength corresponding to the absorption peak of the administered drug. The
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absorption of photon energy by the sensitizer induces a photochemical reaction that results
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in cellular damage leading to cell death4. Cancer cells retain more photosensitizer inside
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them than surrounding normal cells after a specified amount of time has passed, causing a
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relative selectivity regarding this treatment5. Additional advantages of PDT are that it can
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induce apoptosis in cancer cells, with no effects in the extra-cellular matrix that remains
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forming a scaffold for the surrounding normal tissue to advance over and it has vascular
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mediated effects that contribute to tumor control4-6.
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PDT is a local treatment modality. Its application can be repeated more than once to the
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same area without accumulative effects7, 8. It does not negatively affect other treatment
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modalities, such as radiation or chemotherapy, leaving further treatment options open.
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All the characteristics described, in addition to the initial favorable experiences
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communicated by other groups4, 5, prompted us to perform a feasibility study of PDT in
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brain tumors. Initially porfimer sodium (Photofrin™, Pinnacle Biologics, Bannockburn IL,
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USA) was chosen4, 5. When second-generation photosensitizers were ready to use, we
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switched to temoporfin (meta-tetrahydroxyphenylchlorin –mTHPC-, Foscan™ Biolitec,
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Jena, Germany)9-11. mTHPC has a deeper penetration in brain tissue and it is cleared from
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the skin much faster than porfimer sodium.
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PATIENTS AND METHODS
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Study Subjects
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Patients diagnosed with primary brain tumors and neither contraindications for general
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anesthesia nor brain surgery were included. After death of two patients with thalamic
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tumors, protocol was modified, excluding patients with thalamic and brain stem locations. 4 Page 4 of 17
Study was reviewed and approved by the Hospital Ethics Committee. Written informed
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consent and Compassionate Use approval from Spanish Health Ministry were obtained for
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each patient according to Spanish regulation.
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PDT Therapy
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Forty eight hours before the surgical procedure, porfimer sodium was administered at a
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dose of 2 mg/kg body weight, through an intravenous drip line. The infusion lasted over 30
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minutes. Photoactivation of porfimer was obtained during surgery by exposure of the
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residual cavity to a non-thermal light at a wavelength of 630 nm, provided by a Ceralas
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PDT 630 Diode Laser (CeramOptec GmbH, Bonn, Germany). The light dose administered
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in this study was 75 J/cm2.
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mTHPC was administered 96 hours before surgery, at 0.15 mg/kg body weight, into a thick
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vein of the arm for 6 minutes. Photoactivation of mTHPC was obtained during surgery by
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exposure of the surgical cavity to a non-thermal light at a wavelength of 652 nm provided
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by a laser Ceralas PDT 652 (CeramOptec, Bonn, Germany). The light dose administered
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was 20 J/cm2.
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Usually post-excision cavities vary in size and are irregular in shape. The Neurosurgeon
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calculates the amount of light to be delivered to the treatment site with the assistance of
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both Radiotherapy and Medical Physics specialists. Two optical fibers were used, alone or
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in combination: one designed to produce an uniform circular field, suitable for illumination
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of flat surfaces and one diffuser fiber for obtaining a spherical field. Personalized fields
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were calculated for every patient with the aim of avoiding dark zones and overdosed ones.
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Once in place, the fibers were maintained in the adequate position by means of a
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mechanical arm.
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According to the protocol and the recommendations of the manufacturers, an illustrated
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booklet explaining detailed written guidelines for light exposure was provided to the
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patient, families and referring physicians, making them fully aware about the importance of
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complying with the light exposure requirements in PDT.
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Surgical procedure
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All pre-operative studies were performed before administering the photosensitizing agent.
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The surgical procedure took place 48 hours after porfimer sodium administration and 96
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hours after mTHPC administration, respectively.
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Craniotomy with radical tumor resection under microscopic guidance was performed. Once
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the surgical removal of the tumor was finished, a laser light was applied to the tumor bed to
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destroy the remaining tumor cells invading the normal looking brain tissue. Light was
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delivered with a laser at 630 nm, 75 J/cm2 in porfimer sodium patients and at 652 nm, 20
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J/cm2 in the mTHPC ones. While the laser light was applied the surgical cavity was cooled
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with a continuous infusion of Intralipid™ (Fresenius Kabi, Barcelona, Spain) at a
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concentration of 2%, diluted in saline serum. Standard procedures for safe laser use were
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strictly followed. In the operating room no direct light was used and the areas of the patient
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not exposed in the surgical procedure were covered with thick blankets. In the surgical
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field, the non-tumor areas were covered with moist gauzes. Afterwards the wound was
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closed in the usual manner. Once in the ICU, patients were kept in a special room with no
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natural sunlight.
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Post-surgery procedure
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Patients left the hospital usually 5-7 days post-op, at night, after sunset. Once at home,
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sunlight was avoided until 4 weeks (porfimer sodium) or 2 weeks (mTHPC) had elapsed
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since the administration of the photosensitizing agent. Patients’ individual sensitivity to
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light was tested. In any case patients were instructed to observe precautions to avoid intense
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sunlight exposure for the first 7 days.
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Post-operatively, patients received temozolomide (TMZ)-based chemotherapy and
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radiotherapy (RT, 60 Gy) according to Stupp protocol2, 3. In case of progression to previous
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TMZ and/or RT, they received intraarterial cis-platinum and bevacizumab. Radiosurgery
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was considered for small recurrences.
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Patients were evaluated with physical examination, blood test including hemogram and
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basic biochemistry and MRI at 1 and 3 months and then at 3 months interval until relapse
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or death.
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Statistical analysis
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Data are reported as means and 95% confidence interval (CI). All statistical tests were
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performed using the SPSS 17.0 software (SPSS, Chicago, IL, USA). The survival data were
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analyzed by Kaplan-Meier method.
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RESULTS
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From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of
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49 years (range 13 to 70) diagnosed of primary brain tumors were treated with PDT.
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Histologies were GBM (n=20), anaplastic astrocytoma (AA, n=10), low grade astrocytoma
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(LGG, n=4), oligodendroglioma (OD, n=7, 4 anaplastic). In 7 patients PDT was repeated at
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the time of the relapse, and for the purpose of analysis of progression-free survival (PFS)
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and overall survival (OS) they have been considered as separate procedures. In 22 episodes
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PDT was part of the initial treatment and in 26 episodes was part of the treatment at relapse.
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Therapy side effects
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Two patients with thalamic tumors treated at the initial phase of the study died in early
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post-op period. A 40-y old male diagnosed with GBM of left thalamic region received PTD
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with Photofrin after a complete resection. He presented massive edema at the end of the
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procedure, refractory to aggressive antiedema measures. The other, a 40-y old male
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diagnosed with AA of the left thalamic region, was operated, leaving a plaque of residual
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tumor close to the internal capsule. He received PTD with Photofrin. Two days later he
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presented massive and refractory edema. We decided to add thalamic or brain stem location
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as absolute exclusion criteria. Otherwise, no other cases of massive edema were observed.
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Mild postoperative brain edema was adequately controlled with corticosteroid treatment.
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Neurologic post-operative deficits occurred in 5 patients (4 hemiparesia, 1 hydrocephalus, 1
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ptosis). Three patients with hemiparesia recovered in 3 to 17 days with dexametasone and
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mannitol; the fourth continues alive but with residual right hemiparesia, 23 months after
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surgery. The hydrocephalus required surgical correction with brain-abdominal derivation.
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Most patients complained of moderate pain in the operated area in the first days after
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treatment, which could be adequately managed with common analgesics.
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One scalp burn requiring plastic surgery with cutaneous graft was observed. Other
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cutaneous toxicities were one case of blisters on the forearm and other of erythema in
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forearm, caused by a negligent observation of specific protective measures about light
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exposure. A case of burn on the thumb fingernail was also observed, induced by the
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pulsoxymeter in ICU. Since then, the pulsoxymeter was changed of finger every hour and
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not used when the patient was fully awake. Slight dermatitis along the course of the vein
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used for the injection of the photosensitizer was almost universally observed. Dermatologic
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complications were usually well managed with conservative treatment and resolved without
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sequealae.
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Survival
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Median PFS observed was 10 months for GBM (95% confidence interval 5.7-14.3), 26
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months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS
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was 9 months for GBM (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50
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months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is
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due to 1 patient with GBM and 2 with AA not censored for PFS because they die from
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causes other than tumor progression (1 pneumonia, 1 cardiomiopathy, 1 sepsis). Median OS
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since first diagnosis was 17 months for GBM (95% CI 15.2-17.8), 66 months for AA (95%
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CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8) (see Figure 1).
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Four patients are alive at the moment without evidence of active disease: one patient with
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OD, treated with porfimer sodium at the third relapse and with mTHPC at the fourth relapse
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(238 months since initial diagnosis), one with LGG treated with porfimer sodium in the
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initial surgery (152 months since first diagnosis), one with OD, treated with mTHPC at the
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third relapse after two previous surgeries (142 months since initial diagnosis), and the last
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one with LGG, treated with porfimer sodium in the initial surgery and with mTHPC at
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relapse (132 months since first diagnosis).
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In several cases of high grade glioma a particular pattern of progression was observed. It
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consisted in tumor growth in points of the surgical bed where a non-optimal exposure to the
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laser light was suspected considering its irregular shape as well as recurrence beyond the
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edges of the surgical cavity and/or distant recurrence including the contralateral
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hemisphere.
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In 22 episodes PDT was part of initial treatment of primary brain tumors and in 26 episodes
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was part of the treatment at relapse. Twenty one procedures were performed using porfimer
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sodium and 27 using mTHPC. Comparisons in efficacy between photosensitizers have not
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been possible due to the heterogeneity of the series and the small number of patients in each
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group to draw definitive conclusions.
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DISCUSION
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Local invasion is characteristic of glioma growth and the most frequent cause of recurrence.
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Around 90% of recurrences diagnosed after initial surgery are localized in a 2-cm area
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surrounding the primary tumor bed1,
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critical for the prevention of glioma recurrence.
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Adjuvant RT, alone or in combination with chemotherapy, has been administered after
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surgery with the aim of killing any tumor cell infiltrating normal brain. Multiple trials with
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different agents and schedules were published with no clear benefit. In 2005, Stupp and
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cols. reported the final results of a randomized trial, showing that the addition of TMZ to
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RT as initial adjuvant treatment prolonged survival of patients with GBM. Five hundred
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seventy-three patients were randomly assigned to either standard RT alone or RT and
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concomitant and maintenance administration of TMZ (TMZ/RT). Patients treated with
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TMZ/RT had a median survival time of 15 months, compared with 12 months for the
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patients initially treated with RT alone. The 2-year survival rate was 26% for the TMZ/RT
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group compared with only 10% in the RT group2, 3.
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Despite these encouraging results, chemo and RT continue to present important limitations.
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RT induces damage and long term effects on the normal brain tissue, a tribute frequently
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paid in the attempt to control tumor growth. New modalities as image modulated RT
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(IMRT) or 3D conformation permit a more selective radiation delivery to the critical areas.
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In selected patients, a second irradiation is feasible, but still far from a dose that could be
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considered curative.
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Some encouraging results were published with high dose chemotherapy in the context of
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multidisciplinary programs and selected patients, but, in general, no significant advances in
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chemotherapy of gliomas have been reported after TMZ13.
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The study AVAglio has demonstrated an improvement in PFS without significant changes
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in OS with bevacizumab, an antiangiogenic drug. It has shown also an improvement in
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quality of life reflected in higher time to neurological deterioration and low corticoids
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consumption in comparison with non-bevacizumab treated patients. On the other hand,
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antiangiogenics interfere with the normal healing of the surgical wounds. Definitive role of
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bevacizumab in gliomas has to be defined14.
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In any case, the current survival rates for malignant brain gliomas treated with surgery,
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radio and chemotherapy has not significantly changed over the years, showing that more
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effective treatment strategies need to be explored.
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Use of 5-amino-delta-levulinic acid or other photoactive agents has been postulated for
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increasing the radicality of the surgical removal, helping to detect residual tumor by its
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luminescence, otherwise not observed by the naked eye7,
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radical removal is not always possible in the brain as the surgical excision of small amount
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of tissue in relevant brain areas can result in significant morbidity.
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PDT has been applied with great success in many areas of medicine. Its first application to
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brain tumors dates back to the 1988 Kaye's team series17. This group treated 56 brain tumor
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cases with a mixed pathology and saw no increase in permanent neurological deficits with
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no technical complexity and with a promising increase in the survival rate. They later
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updated their series confirming initial observations18, 19. Other reports from Canada20 and
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those from Eljamel et al.8, 21-23 in recent years have not only reproduced initial results but
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also have explored modifications in technique in an attempt to improve final results. New
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promising porfirin derivatives are being currently evaluated for clinical use24.
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Data from this study confirm the feasibility of adding PDT to the standard therapy of
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malignant brain tumors. The results found in this series are not inferior to those found in
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literature, in spite of the particular characteristics of the patients. Nineteen of the 41 patients
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were treated at relapse, after one or more surgeries and chemo/RT. The number of patients
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operated with recurrences makes this series more valuable.
8, 15, 16
.Unfortunately such a
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Some LGG can be controlled with standard treatment. Nevertheless, the pre-op diagnosis of
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a LGG is frequently based in stereotactic biopsies and/or radiologic findings, and it has to
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be remarked that an unequivocal diagnosis is obtained only after tumor removal when the
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anatomical location permits it. Mixed tumors, unusual radiologic findings and relapses are
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not uncommon and these were the reasons for including LGG in the study25.
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Local control of the disease has been satisfactory, particularly in LGG. Recurrences in
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GBM often happened at distant sites from the PDT treated surgical bed. In some cases,
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including two of the patients alive at this moment, longer survivals were obtained after re-
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operation with PDT, suggesting that PDT can be repeated with no accumulative effects.
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In young patients the possibility of treating the tumor without RT is particularly useful,
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since it avoids the potential for radiation-induced tumors later in life, and prevents the long-
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term sequelae after RT. That is the case of one of our patients treated when he was 13 years
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old for a recurrent OD. In spite of not receiving RT is still free of recurrence eight years
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later.
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Both reported deaths were due to strong post-op edema in thalamic region. Patients with
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thalamic and brain stem tumors should be discarded for PDT until more effective methods
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for controlling immediate post-op edema are available.
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mTHPC infusion-related local pain has been repeatedly reported6. In our series we found
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essential that the intravenous injection be carried out slowly (the manufacturer's
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recommendation is over 6 minutes) and in a thick caliber vein of the forearm.
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Photosensitivity skin reactions are avoidable. Minor skin photosensitivity reactions due to
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exposure to natural sunlight might be completely avoided by strict compliance of the light
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exposure recommendations. In our series, none was of clinical relevance except for the
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scalp burn requiring plastic surgery. There are other concerns such as photosensitizer
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extravasation while being injected and subungual burn due to pulse oxymeter, that need
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careful attention of the caring team to avoid them.
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Slight dermatitis along the course of the vein used for the injection of the photosensitizer
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was almost universally observed. The most probable origin is microextravasation, causing
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retention of the drug in perivascular area.
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Although the present and some previous PDT studies are based on a relatively small
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number of patients and in inhomogeneous samples, they suggest an encouraging benefit for
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patients with brain tumors. This study confirms that PDT can be considered as an
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adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors,
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excluding those patients with thalamic or brain stem locations.
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