Photodynamic Therapy

Photodyamic therapy was first used to treat a glioma patient in 1980. Since then, thousands of glioma patients have been treated with this modality at the time of first surgery or repeat surgery. Photodynamic therapy consists of two phases. First, hours prior to surgery, a photosensitizing agent (often porphyrin based) is intravenously injected into the patient and tumour cells selectively take up this agent. Secondly, after surgical resection of the tumour, laser light is applied to the resection cavity. The tumour cells are primarily killed off during this treatment with singlet oxygen, which is a result of the interaction between the photosensitizer and the laser light [1].

An impressive retrospective study of 136 anaplastic astrocytoma and glioblastoma patients (both newly diagnosed and recurrent) treated in Melbourne, Australia between 1986 and 2000 has been published [2].

Most impressively, 29 recurrent anaplastic astrocytoma patients (median age 35) had a median survival of 66.6 months from the time of repeat surgery. By Kaplan Meier estimate, 35% of these patients survived to 15 years beyond repeat surgery. For recurrent anaplastic astrocytomas, this is by far the longest median survival statistic from the time of recurrence that I’ve encountered in the literature for any therapy. 30 newly diagnosed anaplastic astrocytoma patients (median age 38) were also treated with photodynamic therapy at first surgery. Their median survival was 77 months (6 and a half years), which is superior to the median survival seen in most prospective trials. 17 of these patients who received a high dose of over 230 Joules of light per square centimeter had a median survival of about 11 years, as we can see by looking at the Kaplan Meier graph shown in the published study [2]. The results for glioblastoma were not as spectacular as those for anaplastic astrocytoma.

Another retrospective study which included 96 primary glioma patients (grades III and IV) treated with photodynamic therapy at St. Michael’s Hospital in Toronto, showed much less impressive results [3]. In this study, 24 anaplastic astrocytoma patients (median age 44, both newly diagnosed and recurrent) had a median survival of 50 weeks (11.5 months). This is roughly 6-fold shorter median survival than the patients in the previously mentioned study.

If we look at the details of these two studies for comparison, two outstanding differences were the dosage of photosensitizer applied, and the intensity of light used. In the Australian study, patients received 5 mg hematoporphyrin derivative per kg body weight. In the Canadian study, patients received only 2 mg of Photofrin (similar to hematophorphyrin derivative) per kg body weight. An even larger difference occurred in the intensity of light applied. The Australian study used a median dose of 230 Joules of laser light per square centimeter, with only 11% of patients receiving less than 150 Joules. The Canadian study used a median of only 58 Joules per square centimeter, with the highest dose being 150 Joules. This striking difference in laser intensity perhaps explains the equally striking difference in survival outcomes observed between these two retrospective studies.

Clinical trials

There is currently a phase I clinical trial underway of photodyamic therapy for recurrent or progressive malignant brain tumours in patients under the age of 18, and a phase II trial is scheduled to begin in July 2014 for recurrent high grade gliomas. Both are overseen by Harry Whelan at the Medical College of Wisconsin. These trials use one of the three FDA approved photosensitizers, Photofrin, which belongs to the first generation of inefficient photosensitizers.

First generation photosensitizers: hematoporphyrin derivative and Photofrin

Despite being the only photosensitizer approved by the United States FDA for cancer use outside of clinical trials, Photofrin has many drawbacks. Developed from hematoporphyrin derivative about 1983 [4], Photofrin was first approved in Canada for photodynamic therapy of bladder cancer in 1993, and later in the US for esophageal cancer (1995), lung cancer (1998), and Barrett’s esophagus (2003). Over 20 years of research has generated much improved second- and third-generation photosensitizers with superior characteristics, yet Photofrin remains the only commonly used photosensitizer for photodyamic therapy in North America.

The drawbacks of Photofrin:
  • High absorption of light at wavelengths between 350 and 600 nanometres (nm), with a peak between 350 and 450 nm, which overlaps with the sun’s peak daylight intensity (400-600 nm). The optimal photosensitizer should have low absorbance in this spectral range, with high absorbance between 650 and 800 nm.
  • Suboptimal tumour selectivity. Photofrin is taken up by cancer cells only modestly more than normal tissues.
  • Due to the two characteristics mentioned above, use of Photofrin leads to prolonged skin photosensitivity, requiring avoidance of direct sunlight for a month or more post-treatment.
  • Because wavelengths below 600 nm have very poor tissue penetration, a laser light wavelength of about 630 nm is used clinically, as Photofrin has a minor absorption peak there. At this compromise wavelength, Photofrin still has poor light absorbance, combined with poor tissue penetration confined to a few millimetres [5]. Much of the incoming light is absorbed by hemoglobin at wavelengths below 650 nm.

Unfortunately, outside of clinical trials, Photofrin is the only approved option for non-topical cancer applications of photodynamic therapy in North America. Improved photosensitizers which have been approved in other countries will be discussed soon.

Second-generation photosensitizers

Second-generation photosensitizers were designed to reduce or eliminate the flaws and problems associated with first-generation Photofrin. As a representative of this class, the chlorin derivative talaporfin sodium (trade name Laserphyrin, also known as NPe6 or LS11) was approved in Japan for photodynamic therapy of early-stage lung cancer in 2003. Talaporfin sodium is a significant improvement over Photofrin in several ways:

  • Reduced skin photosensitivity, reducing the period of light shielding down to two weeks or less (compared to at least four weeks with Photofrin). This is partially due to a quicker excretion of the photosensitizer from the body [6].
  • An absorption peak at the 664 nm wavelength allows deeper penetration of light into tissue and less absorption of the incoming light by hemoglobin.

In a study published in 2013 in the Journal of Neurosurgery [7], Japanese investigators prospectively studied talaporfin sodium based photodynamic therapy of 27 malignant brain tumour patients at the time of surgery. 13 newly diagnosed glioblastoma patients were treated with surgery and photodyamic therapy. For these 13 patients, median age was 49, mean age 46, and tumours were predominantly (53.8%) located in the frontal lobe. Median ECOG performance status (a rating of general functioning, 0= best) was 1, 5/13 (38.5%) had a total resection, and 8/13 (61.5%) had a subtotal resection. The reported six-month progression free survival and 12 month overall survival rates for the newly diagnosed glioblastoma patients were 100% and 100%. Median overall survival was 24.8 months, median progression-free survival was 12 months and median local progression-free survival was 20 months. While this was a small group with younger median age than that usually seen in glioblastoma trials, such a high 12-month overall survival rate, and high median progression-free survival are rarely seen in glioblastoma trials.

References
  1. Photodynamic therapy of cerebral glioma – a review. Part II – clinical studies. Stylli et al. 2006.
    READ SOURCE DOCUMENT (abstract only. email me for PDF)
  2. Photodynamic therapy of high grade glioma – long term survival. Stylli et al. 2005.
    READ SOURCE DOCUMENT (PDF)
  3. Photodynamic therapy of brain tumors – a work in progress. Muller et al. 2006.
    READ SOURCE DOCUMENT (abstract only. email me for PDF)
  4. Advance in photosensitizers and light delivery for photodynamic therapy. Yoon et al. 2013.
    READ SOURCE DOCUMENT
  5. Dye sensitizers for photodynamic therapy. Ormond et al. 2013.
    READ SOURCE DOCUMENT
  6. Photodynamic Therapy Using Talaporfin Sodium and Diode Laser for Newly Diagnosed Malignant Gliomas. Akimoto. 2013.
    READ SOURCE DOCUMENT
  7. Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors. Muragaki et al. 2013.
    READ SOURCE DOCUMENT (abstract only. email me for PDF)