Conclusion This study is the first to evaluate the relationship between liposomal DOX formulations and their AE profiles.
References 1. Clinical development of liposome based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomedicine. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.
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Analysis of neuropsychiatric adverse events in patients treated with oseltamivir in spontaneous adverse event reports. Hyperglycemic adverse events following antipsychotic drug administration in spontaneous adverse event reports. J Pharm Health Care Sci, ; 1, Quantitative signal detection using spontaneous ADR reporting. Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome?
Non-pegylated liposomal doxorubicin in metastatic breast cancer patients: a valuable therapeutic option requiring caution. J Oncol Pharm Pract. Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology Williston Park. The process of cell division, whether normal or cancerous cells, is through the cell cycle. The cell cycle goes from the resting phase, through active growing phases, and then to mitosis division.
The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division. If the cells are unable to divide, they die. The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink.
They also induce cell suicide self-death or apoptosis. Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific. Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific.
The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective.
This is why chemotherapy is typically given in cycles. Chemotherapy is most effective at killing cells that are rapidly dividing. Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells. The "normal" cells will grow back and be healthy but in the meantime, side effects occur. Different drugs may affect different parts of the body.
Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms.
The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.
Squares are ORs of alopecia for separate trials. The incidence was counted for all grades of neutropenia. The odds ratios of eight of the nine trials are in favor of the liposomal doxorubicin Figure 4. One study showed similar toxicity on both arms. The pooled result is in favor of the liposomal doxorubicin with an Odds ratio of 0.
Comparison of odds ratio in neutropenia. Squares are ORs of neutropenia for separate trials. The odds ratios of all 9 studies were analyzed. The odds ratios of Chan, Dimpoulos, Gill, Harris and Northfelt studies were in favor of the non liposomal anthracyclines.
The odds ratios of Batist, Judson, Northfelt and Rifkin studies were in favor of the liposomal arm. The overall OR for the pooled analysis of the nine trials was 0. Comparison of odds ratio in febrile neutropenia.
Squares are ORs of febrile neutropenia for separate trials. The other hematological toxicities anemia and thrombocytopenia were also in favor of the liposomal arm. The odd ratios of anemia and thrombocytopenia were 0.
The incidence of nausea and vomiting was less with the liposomal arm with an odd ratio of 0. This meta-analysis included nine randomized controlled trials comparing liposomal and conventional anthracyclines. Previous studies [ 28 ] have shown that the incidence of anthracycline induced CHF is directly proportional to the cumulative dose of anthracyclines.
In this meta-analysis, the odds ratio reveals the incidence of cardiotoxicity to be significantly lower with the liposomal anthracyclines. This study therefore confirms that the liposomal anthracyclines offer an alternative to conventional anthracyclines for patients with previous history of cardiac disease, elderly patients, and prior use of anthracyclines who are at high risk to develop cardiac toxicity.
The safety profile with high cumulative dose range of liposomal anthracyclines favors the use of liposomal anthracyclines on patients who were previously treated with anthracyclines. The cardiac safety profile of the liposomal formulations of anthracyclines suggests the potential to use it in combination with trastuzumab in HER2 positive breast cancer.
The incidence of hematological toxicity of all grades was lower with liposomal anthracyclines. The incidences of neutropenia were significantly lower with liposomal anthracyclines, although there were no significant differences in febrile neutropenia. The lower incidence of myelosuppression makes the liposomal anthracyclines particularly more desirable for elderly patients.
PPE is a dose limiting toxicity of pegylated liposomal doxorubicin, doxil, which is the only liposomal doxorubicin approved in USA, even though the meta-analysis did not show significant differences in PPE. The main limitations of the study are the heterogeneity of study groups. Though there was no difference within the study in each group, there were variations among different studies based on various factors.
The primary cancer treated was metastatic breast cancer in four trials, multiple myeloma in two trials, AIDS related Kaposi sarcoma in two trials and metastatic soft tissue sarcoma in one trial.
Due to the different tumor types, the study drugs varied in the dose, frequency and number of treatment. However, the intergroup variations have a limited effect on our meta-analysis due to the fact that each trial is randomized and well controlled. There are no variations among the two groups within the studies. The existence of heterogeneity among the study group was evaluated using the chi-squared analysis. The extent of heterogeneity was assessed using the I-squared analysis.
Moderate to high heterogeneity was noted among the study groups. To minimize the bias, we used random effects models for the studies with high heterogeneity, as recommended and performed by many statisticians and meta-analysis publications [ 29 — 31 ]. Liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated favorable toxicity profiles with better cardiac safety and less myelosuppression, alopecia, nausea and vomiting compared with the conventional antracyclines.
The better therapeutic index of liposomal anthracyclines without compromising the efficacy makes it a favorable choice over conventional anthracyclines in elderly patients, patients with risk factors for cardiac disease and patients with prior use of anthracylines.
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