Delivery Of Cancer Chemotherapy Research Articles

Membrane effects from ultrasound interactions with microbubbles—From drug delivery to mechanotransduction

Ultrasound is an ideal modality to interact noninvasively with tissues deep within the body because of its significant penetration depth. However, noninvasive low intensity ultrasound on its own has difficulty creating mechanical forces necessary for localized activation of cells through mechanotransduction or rupture of non-echogenic drug delivery vehicles. Lipid-coated microbubbles are particles that provide a high-level of impedance contrast with the surrounding tissue and undergo significant size oscillations when exposed to ultrasound. This imparts mechanical forces on nearby lipid membranes which can be used for a variety of applications. Here, I will discuss the mechanical forces that are created by ultrasound/microbubble interactions that can be used to transduce mechanical forces across intact membranes for cellular activation, and to rupture membranes of drug delivery vehicles. I will also discuss the interaction of lipid debris left over from by microbubble destruction with cell membranes. The cell activation and vehicle release show promise for clinical applications including neuromodulation and cancer chemotherapy delivery.

Polymer-Lipid Hybrid Systems: Scope of Intravenous-To-Oral Switch in Cancer Chemotherapy

Cancer chemotherapeutic administration by oral route has the potential to create “hospitalization free chemotherapy”. Such a therapeutic approach will improve patient compliance and significantly reduce the cost of treatment. In current clinical practice, chemotherapy is primarily carried out by intravenous injection or infusion and leads to various unwanted effects. Despite the presence of oral delivery challenges like poor aqueous solubility, low permeability, drug stability and substrate for multidrug efflux transporter, cancer chemotherapy delivery through oral administration has gained much attention recently due to having more patient compliance compared to the intravenous mode of administration. In order to address the multifaceted oral drug delivery challenges, a hybrid delivery system is conceptualized to merge the benefits of both polymeric and lipid-based drug carriers. Polymer-lipid hybrid systems have presented various significant benefits as an efficient carrier to facilitate oral drug delivery by surmounting the different associated obstacles. This carrier system has been found suitable to overcome the numerous oral absorption hindrances and facilitate the intravenous-to-oral switch in cancer chemotherapy. In this review, we aimed to discuss the different biopharmaceutic challenges in oral delivery of cancer chemotherapy and how this hybrid system may provide solutions to such challenges.

The Medicare Prescription Drug Improvement and Modernization Act and the delivery of cancer chemotherapy

Pharmacists' increasing need for assistance in understanding the financial aspects of cancer treatment in physician office-based and hospital outpatient-based cancer programs, and the impact of changes in Medicare reimbursement rates associated with the Medicare Prescription Drug Improvement and Modernization Act (MMA) on providers of cancer chemotherapy and patients are discussed. Most cancer drugs are covered under Medicare Part B, although there is limited coverage under Part D. The financial burden on patients of paying for cancer chemotherapy has increased under both Part B and Part D. Changes in the basis for Medicare reimbursement for chemotherapy have reduced payment rates, and some currently available cancer drugs are reimbursed less than their actual cost. Pharmacy costs (i.e., overhead) were not accounted for in MMA, and quantifying these costs and finding a way to pay for them present challenges. Pharmacists need to be involved in discussions about Medicare spending and cost sharing by providers and patients. Providing cancer chemotherapy presents patients and providers with unique financial challenges. Pharmacists have a stake in and need to provide input into Medicare decisions about reimbursement for cancer chemotherapy and cost sharing by patients and providers.

1612 POSTER Living with a peripherally inserted central catheter for the delivery of cancer chemotherapy: a phenomenological study

1612 POSTER Living with a peripherally inserted central catheter for the delivery of cancer chemotherapy: a phenomenological study

Myelotoxicity and Dose Intensity of Chemotherapy: Reporting Practices From Randomized Clinical Trials

Delivery of cancer chemotherapy is often limited by myelotoxicity, primarily neutropenia. As part of an effort to create a model to predict the risk of chemotherapy-induced neutropenia, we reviewed the reports of randomized clinical trials with more than 50 patients per arm in early-stage breast cancer (ESBC) and non-Hodgkin's lymphoma (NHL) published between 1990 and 2000. We observed that no hematologic toxicity data were reported in 39% and 34% of the ESBC and NHLtrials, respectively. The remaining trials reported on hematologic toxicity in 16 different ways. When reported, rates of neutropenia, leukopenia, and hematotoxicity varied widely with the same and similar chemotherapy regimens. Dose-intensity data were not reported in 39% and 54% of ESBC and NHL trials, respectively. The majority of the remaining studies reported incomplete dose-intensity data such as percentages of patients completing all cycles or receiving a given percentage of planned dose intensity. Only 28% reported the mean or median relative dose intensity received by patients. Based on this review, we conclude that current practices for reporting chemotherapy treatments are inadequate for describing the risk of chemotherapy to patients or for quantitatively assessing the risk of treatment alternatives. We recommend that standard procedures for documenting and reporting hematologic toxicity and dose intensity in cancer chemotherapy trials be required for publication of chemotherapy trials.

Inducible expression of herpes simplex virus thymidine kinase increases sensitivity to ganciclovir but does not enhance bystander effect in breast cancer cells

Delivery of cancer chemotherapy directly to the cancer cell has great appeal. Previous studies using adenoviral transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) in an ascites model of breast cancer was successful in reducing tumor burden and prolonging life. However, increasing the viral dose resulted in increased toxicity and host mortality emphasizing the need for an improved therapeutic ratio. To test the hypothesis that enhancement of HSV-tk gene expression would lead to increased sensitivity to GCV and improved bystander effect, we created breast cancer cells expressing HSV-tk under the control of the inducible tetracycline promoter. Using this system, we could inducibly increase gene expression and biochemical activation of HSV-tk. These increased levels of HSV-tk decreased the IC50 to GCV nearly 50-fold. However, the bystander effect was not enhanced by increasing HSV-tk gene expression. We conclude that increased HSV-tk gene expression improves sensitivity to CCV. However, additional measures, such as increased gap junction communication, will likely be needed to enhance the bystander effect and the therapeutic efficacy of this strategy.

Chronotherapy for gastrointestinal cancers.

Chronotherapy consists in the administration of medicines according to biological rhythms. Further insight into the mechanisms of the circadian system has led to adapting the delivery of cancer chemotherapy to rhythms in drug metabolism or cell proliferation. The pharmacology of anticancer agents has long been known to vary largely and predictably according to dosing time in mice or rats. Portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a sufficiently large patient population. This demonstration was achieved using a 5-day infusion of 5-fluorouracil, leucovorin, and oxaliplatin in patients with colorectal cancer metastases. A further innovation was that oxaliplatin, a new drug whose activity in this disease was first shown using chronomodulated infusion, was incorporated early in this novel three-drug regimen, in view of the good tolerability of this administration schedule. The fully ambulatory nature of treatment courses was an additional constraint put on chronotherapy. More than 1000 patients with metastatic gastrointestinal malignancies have now received chronotherapy protocols in several countries from North America or Europe. Results have clearly indicated that this approach improved chemotherapy tolerance and allowed safe increases in drug doses. A clinical phase III trial compared a flat versus the chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in both tolerability and response rates in patients with metastatic colorectal cancer receiving chronotherapy. This approach may also be beneficial to patients with other gastrointestinal malignancies, and it was amenable to combination with surgery and radiotherapy. It also appeared suitable for devising potentially more active dose-intensive yet safe regimens. Incorporation of chronopharmacology into the development stages of new drugs may improve their safe use to the greatest benefit of both cancer patients and new drug development, as was done for oxaliplatin.

Optimal delivery of dose in cancer chemotherapy with the support of haematopoietic growth factors

The delivery of cancer chemotherapy is often non-optimal because of dose reductions and delays related to various toxic effects. These result in a decrease of the dose intensity as well as of the relative dose intensity of a given regimen compared to a reference protocol. In retrospective studies, such modifications have been shown to negatively influence the therapeutic results in many clinical situations. The ability of haematopoietic growth factors to reduce chemotherapy-related neutropenia and its associated infectious complications allows better dose-on-time delivery of the chemotherapeutic drugs. The potential therapeutic impact of this effect remains to be determined in prospective studies.

The delivery of cancer chemotherapy by constant venous infusion. Ambulatory management of venous access and portable pump.

Fifty chemotherapy trials with 5-fluorouracil; mitomycin C; vinblastine; Adriamycin; and cis-platinol were initiated employing constant (24-hour) intravenous infusion for protracted periods (14-94 days). The use of the tunneled subclavian line for greater than 2200 patient days was associated with minimal complications and no instances of thrombosis or infection were observed. The use of an ambulatory infusion pump was associated with a pump efficiency of greater than 85% in 38 of 39 evaluable trials. Only four of 50 trials were associated with excess drug infusion and in no instance was a drug complication encountered. Constant infusion cancer chemotherapy is feasible, reliable, and safe. Objective tumor regression is observed but the superiority of this drug schedule over the standard intermittent bolus schedule is yet to be determined. Nonetheless, drug toxicity patterns are altered substantially and, in particular, gastrointestinal side effects of chemotherapeutic drugs may be eliminated without compromising cumulative dose.