Polymer-conjugated paclitaxel as a radiosensitizing agent--a big step forward for combined modality therapy?

The paper in this journal by Milas et al. (1) presents in vivo murine data for a combined modality therapy (CMT) treatment program consisting of polymer-conjugated paclitaxel [Poly(L-glutamic acid)-paclitaxel conjugate; PG-TXL] given concurrently with fractionated external beam radiation therapy. The improvement in tumor control for the combined treatment is quite remarkable compared with the individual treatments, as well as in comparison with other in vivo data for CMT of any type. This innovative mechanism for drug delivery achieves a high degree of spatial localization of chemotherapy within the tumor, which contributes to the efficacy of this preparation as a pure chemotherapeutic agent (2). Yet it seems that this compound has an even greater benefit when used as a novel method for delivering chemotherapy as a radiosensitizer. The intriguing preclinical data suggest a large potential benefit of this paclitaxel preparation compared with standard intravenous chemotherapy in the clinical delivery of CMT. The efficacy and usefulness of taxanes as radiosensitizers have been supported by a substantial quantity of experimental and clinical data since the initial characterization of the interaction (3). Despite the toxicity, both local and systemic, general principles have been derived for optimal use of paclitaxel as a radiosensitizer. The principal toxicity of paclitaxel is systemic, which is not an issue for PG-TXL. The plasma half-life of paclitaxel is such that ideal delivery for radiosensitization is achieved with frequent drug dosing, another area where the PG-TXL has demonstrated a beneficial profile. As we evaluate the potential of this novel mechanism for drug delivery of a radiosensitizing agent, we need to consider what advantages and disadvantages it presents compared with standard intravenous preparation and how it relates to other targeted therapies. One of the fundamental reasons for the success of radiation therapy as a solid tumor treatment modality is our ability to spatially define and limit the volume irradiated, thus limiting the normal tissue exposed to potential morbidity of treatment. If we consider the use of PG-TXL alone, it achieves spatial localization of drug distribution in the tumor—something that is typically lacking in systemic therapy. Employing PG-TXL as a radiation sensitizer adds another level of spatial localization to radiation-based localregional therapy. There is an additional mechanism of spatial cooperation between drug and radiation localization: In vivo laboratory data indicate that radiation adds to the accumulation of drug within the tumor by modification of the tumor bed vasculature. Looked at in aggregate, this combination of therapeutic modalities achieves spatial localization by multiple mechanisms: Radiation limitation of the physical extent of dose delivery, drug concentration of dose in the tumor, and radiation modification of the concentration of drug in the tumor. Although PG-TXL is delivered as a systemic agent, it is concentrated in the tumor based on the differential structure of the tumor vasculature compared with normal tissue vasculature. This mechanism of deposition of the polymer in tumor is in marked contrast to the polymer-based delivery system in clinical use, Gliadel, which delivers a slow release of BCNU for primary brain tumors (4). Although a similar differential between local and systemic drug concentrations is obtained with Gliadel, it requires implantation at the site of the tumor resection bed to achieve this. Distribution of the drug in this manner is optimal for radiosensitization, because maximal drug concentrations are achieved at the irradiated tumor site occurring over an extended period of time. In addition, the PG-TXL formulation leads to a dramatic increase in the therapeutic ratio compared with standard paclitaxel delivery as a consequence of the increased local concentration of drug. For example, Milas et al. demonstrate that the quantity of drug delivered to the gastrointestinal system is inconsequential in terms of radiosensitization, compared with that achieved for the tumor. No excess GI toxicity was detected in a comparison of radiation, with or without PG-TXL. The polymer conjugated approach yields a high degree of drug specificity by employing the tumor vasculature to concentrate the drug. It is instructive to consider this in the context of tumor specificity for cytotoxic agents, because this is one of the driving forces behind our current search for targeted cytotoxic agents. The PG-TXL achieves a high degree of tumor specificity, although mech-