**Author details**

delivery of CB via CED but also provided important information about the pathophysiologi‐ cal mechanism underlying the adverse events observed in the clinical trial with CED, which is helpful to minimize the complications in further studies. A multicenter Phase III trial (Phase III Randomized Evaluation of CED of IL13‐PE38QQR Compared to Gliadel® Wafer with Survival End Point in GBM Patients at First Recurrence, PRECISE) investigated the efficacy of CB infused via CED (75). Two hundred ninety‐six patients with recurrent GBM were random‐ ized to receive CED of CB or Gliadel® wafers. Unfortunately, although there was statistically significant improvement in progression‐free survival between patients treated with CB and those with Gliadel® wafers (17.7 vs. 11.4 weeks, *p* = 0.0008), no survival benefit was found, with the median survival of 11.3 months for CB and 10 months for Gliadel® wafers for the efficacy evaluable population (*p* = 0.310). But it is worth noting that 32% of catheter placements were not performed per protocol specifications and drug distribution was not evaluated with image monitoring. These two limitations may be possible explanation for the failure of the trial. Lately, Sampson and colleagues (76) retrospectively analyzed the catheter positioning and drug distribution in the PRECISE trial using BrainLAB iPlan Flow software that was not available during the trial. The study demonstrated that more than 50% of catheters did not meet all positioning criteria among 174 cases with sufficient data. In addition, the simulation analysis revealed that the average coverage volume was very low, with only 20.1% of the 2‐ cm penumbra surrounding the resection cavity covered on average. Therefore, lessons learned from PRECISE trial clearly indicate that the accurate catheter positioning and the real‐time monitoring of drug distribution are critical for the success of interstitial drug delivery via CED.

Until now, many other agents such as monoclonal antibodies (e.g., 131I‐chTNT‐1/B mAb), oligonucleotides (e.g., TGF‐beta2 antisense oligonucleotides) and viruses (e.g. LSFV‐IL12) have been investigated via CED in early‐stage clinical studies (77–79) and demonstrated benefit in selected patients. Well‐designed randomized trials are required to confirm the efficacy. In the future, so as to fulfill an effective treatment strategy, CED will require optimized infusates, improved catheters, standardization of catheter placement, mathematical models to

Malignant glioma, especially GBM, is still a devastating cancer in CNS. Despite of intensive treatment with neurosurgical resection, radiotherapy, and adjuvant chemotherapy with TMZ, the median survival is less than 2 years. Development of novel strategies against malignant gliomas is of urgent necessity. The advent of interstitial chemotherapy has definitely in‐ creased treatment options for patients with malignant glioma. Local delivery of chemothera‐ peutic agents bypasses the physiological barrier of normal brain, achieving a significantly increased concentration in targeted sites and a minimized systemic toxicity. Gliadel® wafers represent the success of interstitial chemotherapy for malignant gliomas. On the other hand, CED is a promising approach for local drug delivery, but improvement in the techniques is

predict drug distribution, as well as the real‐time monitoring of infusate delivery.

*4.3.3. Future prospects*

330 Neurooncology - Newer Developments

**5. Conclusion**

Ke Sai, Shu‐xin Sun and Zhong‐ping Chen\*

\*Address all correspondence to: chenzhp@sysucc.org.cn

Department of Neurosurgery/Neuro‐oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
