Faculty: Peter Warnke; Ben Roitberg

Residents: Ricky Wong; Javed Khader-Eliyas; Ashley Ralston; Melissa Stamates; Mahua Dey

Articles:

1) LeWitt P, Rezai AR, Leehey, MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar, A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During M, Kaplitt MG, Feigin A. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomized trial Lancet Neurology 2011; 10:309-19

Stamates: LeWitt et al. completed the first multi-center, double-blind randomized trial in gene therapy insertion for advanced Parkinson’s disease to demonstrate any therapeutic effect. Gene transfer of glutamic acid decarboxylase and subsequent GABA production in the subthalamic nucleus (STN) was proposed by the authors as superior treatment to DBS and subthalamotomy when medication fails to control PD symptoms. The authors performed a gene therapy trial under rigorous experimental standards, whereas most such studies are open-label. The relative standardization of stereotactic frame placement and microelectrode recording allowed each center to uniformly infuse the treatment vector (Adeno-Associated Virus – AAV) into each subject’s bilateral subthalamic nuclei. Controls only received partial thickness burr holes and the injection was simulated but did not take place. One patient did not receive bilateral placement, instead having two infusions delivered to a unilateral STN without significant adverse effect, although this was reported to all regulatory boards and could have been remedied with correct coordinates. There were many measured variables of response; the main outcome reported was the motor score of the unified Parkinson’s disease rating scale (UPDRS) and the decrease in score (corresponding to symptom improvement). Patients had to score 25 of a maximum 56 in order to enroll. Despite small sample size (45 patients), the collected data showed statistically significant differences in the GAD group’s UPDRS score, which improved by 8.1 points vs the control group, which improved by 4.7 points. However, the improvement was modest. This study demonstrated successful performance of somatic-cell gene transfer to affect GABA transmission in order to develop a new treatment opportunity for advanced Parkinson’s disease patients. The question is whether further randomized double-blind gene therapy trials on a larger scale will show a benefit of gene therapy that optimizes the GABA outflow when compared to today’s lesioning & electrostimulation. At this time it is not clear to me what the inherent advantage of gene therapy over DBS is. Roitberg: Gene therapy studies have to consider issues of stability of gene expression over time and excessive effects of the gene product with side effects. The bar is set quite high, especially for a therapy that does not treat the cause of the disease or cure it. Existing therapies such as deep brain stimulation (DBS) produce significant benefits that may be hard to beat. On the other hand, a one-time treatment may be less expensive than DBS. Warnke: This is a phase II study, the design is as good as you can get with a study of this type. We must note, though, that this is not gene therapy to stop or change the course of the disease, only to change the behavior of the subthalamic nucleus. It is not an inherently superior or more curative approach compared to DBS. The improvement is small compared to DBS. The authors report no significant change on most outcome scales, except the UPDRS motor, and that improved less than 30%. In DBS the goal is more than 50% improvement to consider the treatment a success. At best we can say that this particular type of gene therapy resulted in a modest and selective effect on the motor score. In general, gene therapy may have a cost advantage over DBS. In most of the world the costly maintenance of DBS make it unfeasible as a treatment for Parkinson’s disease. AAV is a good choice because it can go into any cell and remains quite stable.

2) Gopalan R, Schlesinger D, Vance ML, Laws E, Sheehan J. Long-term Outcomes After Gamma Knife Radiosurgery for Patients With a Nonfunctioning Pituitary Adenoma. Neurosurgery. 2011 Aug;69(2):284-93.

Wong: This is a retrospective study looking at 48 adult patients over 14 years (1990-2004) who underwent Gamma Knife radiosurgery for non-functioning pituitary adenoma. Importantly, all but one of these 48 patients had undergone previous treatment, either surgery, CRT, or both.  The primary endpoints that were evaluated were incidence of hormonal dysfunction and tumor control. Patients were followed using MRI and hormone studies. Tumor volume decrease was found in 75%, with sizes less than 5mL found to have a greater rate of size decrease when compared to tumors greater than 5mL. Rate of delayed endocrinopathy was found to be 31.4% at 60 months, but notably a delayed spike up to 50.7% was found at 120 months. There was also a fairly large rate of visual acuity decline after radiosurgery. Some of the limitations of the study include its patient population: namely 98% (47/48) had previous therapy. Therefore, any conclusions drawn can only be applied to that specific subgroup of non-functioning pituitary tumors. With regards to the treatment being investigated, no details are given regarding the specific parameters used for the Gamma Knife protocols. Some other concerns include their use of a 15% reduction in tumor volume to define clinical response, which is substantially less than the typical 25% normally referenced. This calls into question the statistical significance of their results. Khader-Eliyas: The visual acuity outcome may not have been so poor. There may be a misprint – the authors probably meant “preop” visual deficit. Then only 3 rather than 10 patients suffered visual deficits after their gamma-knife treatment, and related to it. Roitberg: This article offers long term follow up of radiosurgery patients. As such, it is valuable and commendable. Long term studies are difficult yet very relevant for the treatment of chronic disease. I have some general comments, relevant when reading any article critically. The authors indicate that tumor control was better for sizes less than 5 cc. Why is there a cut off at 5 cc? There are mathematical ways to determine if there is indeed a cut-off point separating two distinct populations. Deciding on an arbitrary demarcation may produce spurious results based on a few outliers. A small shift of the arbitrary border may get opposite results. The reality is usually more complex – data analysis should aim to find out real relationships among pieces of data – is there a linear regression? A real separation of two groups into small and large tumors? Is 5 cc a real turning point? Or maybe there is no effect, and significance disappears when a few extreme cases are excluded. The human mind tends to generate and look for patterns; when there is an incentive to see a pattern our natural tendencies are reinforced. Our biases are mostly unintentional. A central part of the scientific endeavor is to try to eliminate biases and look for real patterns. Warnke: This article suffers from several problems, not least among them suboptimal editing. The title is misleading – the article is really about recurrent tumors. The authors criticize fractionated radiation. However, contemporary radiotherapy employing for example intensity modulated radiotherapy has a much reduced risk profile compared to the studies the authors quote making some of the reported morbidity quite historical. Other problems – the study used 15% reduction in tumor volume as a definition of clinical response, much less than the typical 50% reduction criterion. Larger tumors got lower doses, which can also affect the results. The outcome was not great – the endocrine outcome was getting worse over time. There were also adverse changes in vision, although it is not entirely clear to me. Simple reading of the article indicates that 10 patients out of 46 had visual acuity deficits after gamma-knife, although this may be one of the editing problems – maybe there was a misprint. There are also no dose plans, no dose – response curves, and little biological meaning connected to the findings. So, overall it is difficult to assess the benefit of gamma knife for recurrent pituitary adenoma based on this article. One additional learning point: Gamma knife is not the only stereotactic single dose radiation option. LINAC can also be effective. The authors used more than 7 isocenters, creating many hot spots, where necrosis occurs over time. The distribution of radiation with LINAC is more uniform. It is not clear which approach is better. Despite the limitations of this particular article, one thing is clear – there are many developments in radiation and radiosurgery. It has many uses and serious research is needed to define optimal application of radiation. I predict that soon the question regarding the treatment of pituitary adenoma will be – is surgery even necessary?