Dear Omar,

The main concerns of proper sequencing chemotherapeutic agents in a multi-drug regimen include clinical and pharmacokinetic interactions in sequence-dependent combination chemotherapy. Suboptimal sequencing or arbitrary sequencing of combination chemotherapy may result in significant reduction of remission rate and/or higher rate of toxicities such as myelotoxicity.

Below attached two articles for your interest. There are abundant articles in this topic.

In some specific protocols the sequence of drugs given on the same day do matter and the sequence needs to be followed strictly.

Also, in some cases, for example in case of colo-rectal cancer the timing of the infusion of the drug (at what time of the day the drug is given) has been reported to matter in terms of response - the same has been presumed to be related to body's cicardian rhythm.

-Parimal

Dear Dr.Shah,

Yes I have encountered some of these protocols for both improving efficacy and limiting side effects (such as fludara and cytosar in FLAG protocol, Etoposide and holoxan (hydration purposes), and taxan dervatives and cisplatin, etc). However, the general role about the cell cycle specific drugs and cell cycle non-specific drugs, I found no reference about it, and some time I found protocols that oppose these sequence. About the circadian rhythm releated protocols, its actually new to me (I am more involved in hematology protocols and didn't encounter much solid such as colo-rectal cancer), thank you for the information anyway.

The sequence of drug administration may be critical; in many experimental systems, administration of paclitaxel before cisplatin gives additive or synergistic results, whereas the opposite sequence yields antagonism and increased toxicity.

Both synergistic and antagonistic interactions have been described. A chemotherapeutic drug may be modulated by a second agent that has no antitumor activity in its own right but that enhances the intracellular activation or target binding of the primary agent or inhibits the repair of lesions produced by the primary drug. The best example of this synergy is the use of leucovorin (5-formyltetrahydrofolate), which itself has no cytotoxic effect but which enhances the affinity of the binding of 5-FU to its target enzyme, thymidylate synthase, by forming a ternary complex among the enzyme, 5-dFUMP, and folate. This and the paragraph above from: Chapter 1: Clinical Strategies for Cancer Treatment: The Role of Drugs.Cancer Chemotherapy and Biotherapy: Principles and Practice, 5e

Sequential administration of paclitaxel followed by doxorubicin in breast cancer patients is associated with cardiomyopathy at total doxorubicin doses above 340 to 380 mg/m2, whereas the reverse sequence of drug administration did not yield the same systemic toxicities at these doses. From: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology > Topoisomerase Interactive Agents Chapter 13: Principles of Chemotherapy in Gynecologic Cancer;6e. Michael A. Bookman.

Methotrexate (MTX) inhibit two steps in de novo purine biosynthesis, and thereby expands the pool of PRPP available for 5-FU activation. The opposite sequence, 5-FU before MTX, produces unfavorable interaction as 5-FU inhibits thymidylate synthase (TS), blocks the generation of oxidized folates by this reaction, preserves the cellular pool of reduced folates, and negates the impact of inhibition of dihydrofolate reductase by MTX. The benefits of sequencing MTX before 5-FU were readily demonstrated in cell culture and in selected mouse models, but clinical trials results exploring multiple different sequences and regimens yielded conflicting evidence of benefit. In clinical practice, such as with the CMF (cyclophosphamide, methotrexate, and 5-FU) regimen in breast cancer, the drugs are given simultaneously for reasons of convenience. From: Cancer Chemotherapy and Biotherapy: Principles and Practice, 5e; Jean L. Grem, Bruce A. Chabner, David P. Ryan, Raymond C. Wadlow. Chapter 9: 5-Fluoropyrimidines. 

There are also some other sequences as well that have clinical significance.

Hope the above examples suffice.

If you find any regimen with opposite sequences look at the long term and the short term morbidity, PFS, and mortality from pjhase III studies to get the correct sequence.

-Parimal