Ask The Experts Ask a Question Medulloblastoma  12/18/2008   I have a patient who is a 29-year-old male with a 3-cm cerebellar medulloblastoma grossly resected. There was mass effect on the 4th ventricle. Is there any role for chemo? If MRI of the spine is negative for drop mets and if CSF cytology is negative, does the entire spinal axis have to be treated? Response from Advisory Board Member Arnab Chakravarti, MD, Associate Professor of Radiation Oncology, and Chief, Brian D. Silber Laboratory of Radiation Neuro-Oncology at Massachusetts General Hospital/Harvard Medical School, Boston: Medulloblastomas, either adult or pediatric, have a propensity to not only recur locally, but also throughout the cranio-spinal axis. Therefore, the standard of care for these tumors has been resection to the greatest extent possible, followed by cranio-spinal irradiation (CSI), followed by involved-field boost to the resection cavity/gross residual tumor. As CSI has been found to be associated with significant long-term side effects in the pediatric population including adverse effects on growth stature, cognition, secondary tumors, among other long-term side effects, there has been a push towards combining chemotherapy with CSI to lower total CSI dose. This has been shown to produce generally equivalent results compared to higher CSI doses for low-risk disease in the pediatric population. However, there is more sparse data on reduced CSI dose with chemotherapy in the adult population. Therefore, many of these patients are more commonly treated by standard CSI doses (36 Gy), followed by involved-field RT boost (18 Gy). GliaSite for Recurrent GBM  12/16/2008   Is there a role for GliaSite for recurrent GBM (after surgery, RT + temozolomide) if the recurrent tumor can be re-resected? Response from Advisory Board Member Matthew G. Ewend, MD, Associate Professor and Chief, Division of Neurosurgery, University of North Carolina, Chapel Hill: While GliaSite is still being used in Europe, it is no longer commercially available in North America. You could consider alternative local therapy such as BCNU-polymer wafers, which are FDA approved for recurrent GBM or a radiosurgery boost, although strong data for the use of radiosurgery is lacking. In our center, we use the Cyberknife for recurrent glioma only in very carefully selected cases (e.g., small recurrence, exhaustion of other treatment options, patients with a longer survival). Videoclip: Technical Advances in RT   12/15/2008   What might be some future technical advances in radiation therapy? Brief video of neurosurgical/neuroradiation experts discussing proton therapy. Participants: Arnab Chakravarti, MD, Associate Professor of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston Michael A. Vogelbaum, MD, PhD, Associate Director, Neurosurgical Oncology, Cleveland Clinic, Cleveland Susan Pannullo, MD, Director of Neuro-Oncology, Weill Medical College of Cornell University, New York, NY Videoclip: Radiosensitizers   12/12/2008   What is the role of radiosensitizers? Neurosurgeon discusses with colleagues the use of radiosensitizers in improving control rates with whole brain radiation therapy. Participants: Michael A. Vogelbaum, MD, PhD, Associate Director, Neurosurgical Oncology, Cleveland Clinic, Cleveland Arnab Chakravarti, MD, Associate Professor of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston Susan Pannullo, MD, Director of Neuro-Oncology, Weill Medical College of Cornell University, New York, NY Intramedullary Ependymoma  11/11/2008   I have a patient who is a 23-year-old male who has undergone 50% resection of a Grade 2 intramedullary ependymoma that extended from the top of C5 to the bottom of T1. What RT dose would you recommend? Is there any role for chemotherapy? Response from Advisory Board Member William Regine, MD, Isadore and Fannie Schneider Foxman Chair & Professor, University of Maryland Department of Radiation Oncology, Baltimore: In this situation, there is a balance between spinal cord tolerance to irradiation versus tumor control. Based on published experience, 50 Gy given at conventional fractions of 1.8 to 2 Gy/day would be standard. For patients with this type of tumor who are already experiencing neurologic compromise, the clinician should consider an additional 4 to 5 Gy boost to gross tumor volume with minimal margin. The experience with chemotherapy in this setting has been limited in use and result. Use of chemotherapy would therefore remain somewhat investigational. Optimal Length for Temozolomide Regimen  9/10/2008   What is the optimal length of time (and what would be the maximum) to prescribe temozolomide (Temodar®) for a glioblastoma? Response from Advisory Board Member Andrew Lassman, MD, Neuro-Oncologist at Memorial Sloan-Kettering Cancer Center in New York: The optimal number of cycles has not been defined. We know that temozolomide administered concurrently with radiotherapy and then administered for at least 6 monthly cycles after radiotherapy is superior to neither concurrent nor adjuvant temozolomide. (Stupp R, et al. N Engl J Med. 2005;352:987-996.) However, it is unknown whether the adjuvant phase of therapy contributes to the survival advantage, or whether more than 6 cycles is superior to 6 cycles of adjuvant treatment. At least 6 months is optimal, and many neuro-oncologists advise 12-18 cycles. I have also seen occasional patients who take temozolomide indefinitely. However, it is possible that temozolomide can induce myelodysplastic syndrome/leukemia as a late toxicity, and the risk, although small, may be higher if a higher cumulative dose is administered. CED  1/30/2008   What is convection-enhanced delivery and where is this technology headed? Response from Advisory Board Member Michael A. Vogelbaum, MD, PhD, Associate Director, Neurosurgical Oncology, Cleveland Clinic, Cleveland: Definition: Convection-enhanced delivery (CED) is a method by which macromolecules can be directly infused into the interstitial space of the brain parenchyma interstitial. This regional delivery technique involves the stereotactic placement of catheters directly in target tissue and infusion of drug using a continuous pressure gradient over periods of hours to days, thereby circumventing the blood-brain barrier. Preclinical studies in multiple models and clinical studies have shown significant, reproducible and homogeneous distribution of molecules of various sizes. Types of Agents Used: Multiple classes of therapeutic agents have been evaluated clinically using CED. While some conventional agents such as paclitaxel or topotecan have undergone limited clinical evaluation, most trials have involved therapeutic agents designed specifically for delivery via CED. A series of conjugated toxins was developed that, in general, consisted of a bacterial toxin (e.g. Pseudomonas exotoxin, Diptheria toxin) conjugated by either chemical or recombinant methods to a ligand that would bind specifically to glioma cells and spare astrocytes and neurons. The concept was that the bacterial toxin, which required access to the cellular cytoplasm for toxicity, would be internalized only by cells expressing receptors for the ligand. Ligands such as IL-13, IL-4, transferrin and TGF-alpha were selected based upon their relatively high levels of expression on malignant glioma cells. These were used for the initial series of conjugated toxins, and each has been evaluated in the clinical setting. Of these, only the IL-13/Pseudomonas exotoxin conjugate (IL-13PE38QQR) completed evaluation in a Phase III clinical trial. PRECISE: This Phase III trial, named PRECISE (Phase III Randomized Evaluation of Convection Enhanced Delivery of IL13-PE38QQR with Survival Endpoint ), was a randomized study that compared a single infusion of IL-13PE38QQR to insertion of Gliadel wafers in recurrent GBM after a complete surgical resection. The trial, which was reported at the 2007 Annual Meeting of the Society for Neuro-Oncology, was powered to detect a 50% improvement in overall survival, but only a small difference in survival was observed – far too small to be statistically significant given the number of patients included in the trial. As a consequence, the FDA did not approve the drug and the prospect of additional trials in the near future for this drug remains unclear. Potential Advances: One of the major lessons from the PRECISE trial which is being carried forward into the design of trials of other new agents for CED is that investigators currently do not have reliable means by which to evaluate, in real time, the actual 3-dimensional distribution of drug when infused by CED. It has become clear that there is a need to have real-time imaging of drug distribution within the brain in order to correlate clinical response to regional drug dosing, a concept that is not at all unlike what is done to plan and deliver therapeutic radiation. Future trials are likely to include co-infusion of an imaging agent, such as gadolinium-DTPA either encapsulated in a liposome1 or conjugated to albumen.2 Other technical advances that are continuing to evolve include computational methods for predicting the path of drug distribution delivered via CED, based upon the tissue properties as determined by diffusion tensor MR imaging, novel catheter designs which may improve the efficiency of delivery, and drug encapsulation strategies which may produce more prolonged exposure of tumor cells to therapeutic drug concentrations. References 1. Krauze MT, Forsayeth J, Park JW, Bankiewicz KS. Real-time imaging and quantification of brain delivery of liposomes. Pharm Res. 2006;23:2493-2504. 2. Lonser RR, Warren KE, Butman JA, et al. Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg. 2007;107:190-197. Thalamic Masses  8/10/2007   Is there a role for surgery in a patient with Grade III right thalamic mass? Response from Advisory Board Member Matthew G. Ewend, MD, Associate Professor and Chief, Division of Neurosurgery, University of North Carolina, Chapel Hill: When I set out to do surgery, I ask myself what extent of resection I can get. If it’s not a very high degree – say approximately 95% of all the enhancing tissue – then I think there’s really very little benefit to surgery. Since this is not a favorable location, I don’t think surgery has a role in this patient. Response from Advisory Board Member Michael A. Vogelbaum, MD, PhD, Associate Director, Neurosurgical Oncology, Cleveland Clinic, Cleveland: I think you have to look at all the imaging very carefully. Ultimately surgical decisions are guided the same way: Do you think you could remove the mass with a very small risk of producing a neurologic deficit? If not, you shouldn’t do that surgery and a biopsy is fine. As a matter of practice in a situation like this, we usually would do a biopsy first to get a sense of histology but also to do 1p/19q testing in case it’s a co-deleted tumor. Even though we don’t have the data yet to prove that that’s really going to make a difference, I think we have enough compelling data to say that in certain cases we should be guiding our therapies based on 1p/19q co-deletion. Surgery & Radiosurgery  8/9/2007   What is the role of surgery and radiosurgery in malignant glioma? Response from Advisory Board Member Michael A. Vogelbaum, MD, PhD, Associate Director, Neurosurgical Oncology, Cleveland Clinic, Cleveland: There are certain situations in which surgery is clearly of benefit. A patient who has clinically obvious mass effect-related symptoms and is at risk for herniation is going to be significantly helped by surgery as long as it’s a resectable lesion. The controversy comes in when there are smaller lesions that are not producing immediate mass effect-related issues. Does a gross total resection help those patients? A randomized trial looking at that question will probably never be done in the US, but there’s a small study that was done in Scandinavia that showed benefit of surgical resection compared to biopsy, only.1 There are some retrospective data from MD Anderson suggesting that a greater degree of resection – more than 98% of enhancing tumor – results in prolonged survival.2 Overall, there’s an accumulating body of evidence that supports the concept that the more of the tumor that can be removed, the better. Surgery is never going to cure these tumors, however; it’s really just an important first step. In addition to any potential therapeutic benefit, several studies have shown that having a larger tissue sample provides a more accurate histologic diagnosis. Needle biopsy can be misleading if there are regional variations in tumor grade. Having an accurate assessment of the grade can alter treatment and would almost certainly alter prognosis. Surgery also provides the ability to deliver local or regional therapies such as BCNU (carmustine) wafers (Gliadel®); brachytherapy using radiotherapeutic seeds or a balloon implant containing a liquid form of radiotherapy (Gliasite®); and a newer technique called convection-enhanced delivery in which chemotherapy is literally pumped into the brain parenchyma. These are still evolving areas of study. Regarding radiosurgery, that’s a fair question because there is little or no evidence supporting its use in malignant glioma. The Radiation Therapy Oncology Group study 9305 (RTOG 9305) addressed the issue of radiosurgery in newly diagnosed malignant glioma in which radiosurgery was added to standard radiotherapy plus BCNU.3 RTOG 9305 showed no survival benefit and actually saw increased toxicity. Eventually, ongoing trials using magnetic resonance spectroscopy (MRS) or positron-emission tomography (PET) to guide targeting of radiosurgery to treat the worst part of the tumor may help radiosurgery to become more beneficial for malignant gliomas. References 1. Vuorinen V, Hinkka S, Farkkila M, Jaaskelainen J. Debulking or biopsy of malignant glioma in elderly people - a randomised study. Acta Neurochir (Wien). 2003;145:5-10. 2. Lacroix M, Abi-Said D, Fourney DR. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95:190-198. 3. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60:853-860.