When giving gemcitabine (Gemzar) and cisplatin (Platinol), is it better to give gemcitabine first to reduce myelosuppression with every indication or only certain ones and if so which ones? —Annette Baker, ADN
Multiple factors affect the sequence of chemotherapy agents, such as the pharmacokinetic properties of the medication (eg, does it undergo extensive metabolism or is the agent extensively protein bound).1 The effectiveness of drugs with cell cycle-specific mechanisms of action (ie, is the drug only active against cells at a specific point in their growth and division) may be heavily influenced by the sequence of administration, as the order of administration may reduce or increase each drug’s cytotoxicity.
Other studies have demonstrated that the sequence of administration may influence the adverse effects patients experience with a regimen. One well-known example of this is administration of cisplatin and paclitaxel (Taxol); when cisplatin is given before paclitaxel, patients experience increased neutropenia. This effect is reduced when paclitaxel is administered first (without reducing the efficacy of the regimen).
In some instances, sequencing data for one agent is applied to all agents in that class (eg, the data with cisplatin and paclitaxel is extrapolated to carboplatin and paclitaxel regimens).
Optimal sequencing of many chemotherapy regimens is determined using preclinical models (eg, cancer cell lines in research labs), rather than studying the effects of different sequences of administration in humans. If there is data comparing the effects of chemotherapy sequencing in human subjects, the results are typically from smaller dose-finding trials. The recommendation to administer gemcitabine prior to cisplatin is based on results of phase 1 studies in adults with solid tumors, which indicated that this administration schedule may increase the generation of platinum-DNA adducts (potentially increasing efficacy) and reduce neutropenia.1 Thus, this is the sequence that was used for subsequent studies of gemcitabine/cisplatin regimens.
Because of the interactions and effects discussed above, it is critical that chemotherapy medications are administered in the correct sequence. Chemotherapy orders should reflect the intended sequence of administration for agents in the prescribed regimen. If there is a question regarding sequencing for a regimen for treatment of a specific cancer, consult your pharmacist to clarify the appropriate order. In many cases, this can be clarified by referring to the pivotal clinical trial of the regimen in the applicable disease state.
Lisa A. Thompson, PharmD, BCOP, Clinical Pharmacy Specialist in Oncology, >Kaiser Permanente, Colorado.
1. Mancini R, Modlin J. Chemotherapy administration sequence: a review of the literature and creation of a sequencing chart. J Hematol Oncol Pharm. 2011;1(1):17-25.