High-Grade Glioma/Glioblastoma Multiforme: Is There a Role for Photodynamic Therapy?

S-31 Supplement High-Grade Glioma/Glioblastoma Multiforme: Is There a Role for Photodynamic Therapy? Presented by Harry T. Whelan, MD, Medical College of Wisconsin, Milwaukee, Wisconsin Abstract backward glance at the origins of PDT for brain tumors, In the United States, the 5-year survival rate for patients of all ages describes the clinical challenges to its use in the skull, with all types of brain tumors is approximately 20%, with the scale skewed toward even poorer survival in patients with gliomas. Al- and outlines the objectives of his phase I study for PDT though surgery and radiotherapy are primary treatment options, in children with brain cancer, the second most common surgery is rarely curative and radiotherapy has had little impact childhood cancer after leukemia. on overall survival. Predominantly studied in adults with advanced Gliomas are among the most challenging of brain high-grade gliomas, photodynamic therapy (PDT) represents tumor subtypes. The location of a benign tumor in the a paradigmatic shift in the treatment of brain tumors. With no eloquent areas of the brain could potentially render it clear standard of care for brain tumors, PDT may emerge as a potential alternative, although challenges regarding its clinical use inoperable, the presence of a blood–brain barrier limits remain and studies confirming its promise are necessary. JNCCN( the ability of systemically administered medications to 2012;10[Suppl 2]:S31–S34) reach the target site, and the intricate neuronal network makes targeted therapy challenging. Patients with high-grade gliomas (HGGs) in particular have a generally poor prognosis, and surgery is rarely curative. “Photodynamic therapy [PDT] has the potential to The use of PDT for brain tumors such as HGGs provide a great service in an area that is very desperately and glioblastoma multiforme (GBM) moves away in need of that,” pronounced Harry T. Whelan, MD, from the more traditional resection and systemic che- Professor of Neurology at the Medical College of Wis- motherapy methods. With light-mediated activation consin in Milwaukee. With no clear standard of care of a photosensitizer that is selectively accumulated and poor 5-year survival rates, there certainly is room for in the target tissue, PDT causes destruction of tumor improvement in caring for patients with brain tumors, cells through the production of singlet oxygen or su- and PDT may play a future role. From its use in canine peroxide and induces cell damage through direct and models in the mid-1990s to its application in patients indirect cytotoxicity. Therefore, photosensitizers are approximately 10 years later, PDT has been emerging the first critical element in PDT procedures, and the as a topic of interest. In this article, Dr. Whelan takes a activation procedure is the second step, explained Dr. Whelan. Presented by Harry T. Whelan, MD, Professor of Neurology, Bleser Endower Chair, Director of Hyperbaric Medicine, U.S. Navy Professional School Liaison, Officer Captain U.S. Navy, Medical The History of Brain Tumors and PDT: College of Wisconsin, Milwaukee, Wisconsin From Canine Models to Humans Dr. Whelan has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturers of any The role of PDT for brain tumors of the posterior fossa products discussed in this article or their competitors. Correspondence: Harry T. Whelan, MD, Department of Neurology, was originally studied preclinically in a canine glioma Medical College of Wisconsin, 9200 West Wisconsin Avenue, model.1 Dr. Whelan and colleagues1 found that a low Milwaukee, WI 53226. E-mail: [email protected] dose of porfimer sodium (Photofrin) produced tumor © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Supplement 2 | October 2012 S-32 Supplement Whelan kill without significant permanent toxicity of the patient who had a glioma at the brain stem solely brain stem in both the control animals and the ani- with PDT. After a brief period of edema, all brain mals with cerebellar brain tumors receiving PDT. stem clinical findings resolved, suggesting a complete “Children’s brain tumors are more likely to appear PDT effect. Unfortunately, the tumor did recur, but in or near the brain stem; adult brain tumors, es- it led Dr. Whelan to turn his research toward a non- pecially the malignant gliomas, occur in the upper invasive device, which could deliver a therapeutic parts of the brain, the cerebral hemispheres,” ex- dose of light within the 630- to 900-nm wavelength plained Dr. Whelan. range into the tumor-ridden area while maintaining Ten years later, after this success with PDT in a canine model, investigators turned to humans.2 exposure levels low enough to eliminate any damage They tried PDT on a collection of 20 patients with to the overlying tissues. recurrent malignant brain tumors. “These patients With PDT, Monte Carlo methods for model- included a hodgepodge of children and adults with ing scattering and absorption in tissue (Figure 1) are various brain tumors in various parts of the brain with useful to ensure that the appropriate levels of light various drugs,” reported Dr. Whelan. “All of these pa- are delivered to activate the photosensitizing agent. tients were dying of progressive disease after failing The output of the Monte Carlo model is a grid repre- to respond to surgery, radiotherapy, and/or chemo- senting the summation of absorption events within therapy.” As documented on MRI, tumor responses the tissue, explained Dr. Whelan. Based on the ap- were seen in all of the patients, and the mean time to proximation derived via this Monte Carlo model, to 2 tumor progression after PDT was 67 weeks. achieve a therapeutic dose of 5 mW/cm2, the surface “If you subtract out the blood–brain barrier area of a 630-nm pulsed photon source at the scalp breakdown, you still have cell-specific uptake of the would need to be approximately 160 times larger Photofrin,” revealed Dr. Whelan. “Although the than the source used in the simulation, which may vascular effects of PDT are important, they are not the only thing: there is tumor cell-specific uptake. be achievable with a “bonnet” configuration. “With And the longer wavelengths probably penetrate the Monte Carlo simulation, you could get enough somewhat deeper into tissue.” Because long-term light into the deep structures of the brain to have a outcomes of patients with these types of malignant photodynamic effect by beaming in light on the sur- brain tumors are generally poor, Dr. Whelan was face of the head,” he proposed. Through continued pleased to announce that 20% of the patients from investigation, Dr. Whelan deduced that reasonable this study are still alive today. measurements 4-cm deep could be obtained through pulsing the light at higher intensities than a person could tolerate if it were given continuously. How- The Clinical Challenge of Using PDT in ever, this possibility of doubling the usual depth re- the Skull quires additional study, he admitted. A major clinical challenge regarding the use of PDT for brain tumors centers on the need for invasive surgery with an adequate system of light delivery. 0.6 ++ + Currently, no device allows the use of PDT without ++ + 0.5 ++ ++ + ++ + + + ++++++++ direct access to the area of the brain containing the +++ +++ + +++++ + ++++++ ++++ + +++ ++ + + + + ++++ +++ + + ++ 0.4 +++++ + +++ ++ ++++ ++ + + ++ ++ ++ +++ tumor. The PDT technique begins by “drilling a hole +++ + + + + ++ + + +++ + + + + + + + ++ + +++ + ++ ++ 3 + ++ into the skull and scooping out some of the brain +++ 0.3 ++ + + ++ + + ++ + +++ ++ ++ ++++ + +++++ + +++++++ tumor,” explained Dr. Whelan. Only the clearly ne- +++++ +++ , W/cm + +++++ ++++ ++++ ++++ 0.2 +++ ++++++ ++++ crotic tumor is removed; the tumor entangled and +++++ +++ ++++ ++ +++ ++++ +++ + + +++ +++++ + ++++++ infiltrating into the healthy normal brain remains to +++++++ 0.1 + +++ +++++++ + +++ +++++++++ ++++++ +++++ + ++++++ +++ be treated by the PDT. Power Density + + + ++ +++ + + + + + + +++ ++++ + ++ + +++ +++++ + ++ + ++ ++ ++++++++++++++++++ + ++ ++ ++ ++++ + +++++++ + + + + + + + + + + + + +++++++++ + +++ + +++ +++ + ++ + ++ + ++ ++++ + + + + + + + ++ + 0 + + + + + + + + + + Interestingly, through his experience with PDT, 0 132 4 56 he found that it might be possible to obtain a clini- cm cal benefit without surgical resection. He treated one Figure 1 Monte Carlo photon distribution. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Supplement 2 | October 2012 Supplement S-33 PDT in Brain Cancer Treatment HGGs: Rationale for Moving Away benefit was seen in those who received temozolo- From Traditional Interventions mide, radiotherapy, and surgery who had expression HGGs such as anaplastic astrocytoma (AA) and of MGMT [O6-methylguanine-DNA methyltrans- 5 GBM account for between 7% and 10% of pediatric ferase],” he revealed. In one study, patients whose central nervous system tumors, reported Dr. Whel- tumors did not have MGMT promoter methylation an. They often have microscopic tumor extension were less likely to benefit from the addition of te- beyond the “margin,” and historically have been as- mozolomide chemotherapy, compared with those sociated with a generally poor prognosis. Dr. Whelan with methylated MGMT. Therefore, overexpression briefly reviewed some of the disappointing results of MGMT appears to be adversely associated with 4 with traditional interventions for HGGs, and the survival. In addition to overexpression of MGMT, promising

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