| AC | DoxorubicinCCNS(
7
)
Vesicant(
9
)
| CyclophosphamideCCNS(
7
)
| - | - | Compatible in Y(
10
)
Cyclophosphamide is a prodrug catalyzed directly by cytochrome P450, mainly through CYP2B6.(
11
) Doxorubicin is a (moderate) inhibitor of the same enzyme.(
12
) To avoid delayed plasma clearance of doxorubicin due to cyclophosphamide metabolism, it is recommended to infuse doxorubicin before cyclophosphamide.(
5
)
|
| CAF | DoxorubicinCCNS(
7
)
Vesicant(
9
)
| FluorouracilCCS(
7
)
| CyclophosphamideCCNS(
7
)
| - | Compatible in Y(
10
)
Fluorouracil acts in specific cell cycle phases, while doxorubicin and cyclophosphamide are CCNS.(
7
) However, doxorubicin has a high tissue vesicant potential, which reinforces the importance of it being administered first.(
9
)
Cyclophosphamide is a prodrug catalyzed directly by cytochrome P450, especially through CYP2B6.(
11
) Doxorubicin is a (moderate) inhibitor of the same enzyme.(
12
) To avoid delayed plasma clearance of doxorubicin due to cyclophosphamide metabolism, it is recommended to infuse doxorubicin before cyclophosphamide.(
5
)
Regarding fluorouracil and cyclophosphamide, it has been observed that fluorouracil sensitizes the DNA so it can be attacked by alkylating agents.(
13
)
|
| Cisplatin + Gemcitabine | GemcitabineCCS(
7
)
| CisplatinCCNS(
7
)
| - | - | Compatible in Y(
10
)
Gemcitabine is a CCS drug while cisplatin is CCNS, which justifies this infusion sequence.Also, gemcitabine administration (4 or 24 hours) before cisplatin administration proved less toxic, causing less leukopenia.(
14
)
|
| Cisplatin + irinotecan | CisplatinCCNS(
7
)
| IrinotecanCCS(
7
)
| - | - | Compatible in Y(
10
)
Irinotecan is a CCS drug, while cisplatin is CCNS. However, with previous administration of cisplatin, there is an increase in the synergistic effect, with the presence of toxicity regardless of the administration sequence.(
15
,
16
)
|
| Cisplatin + paclitaxel | PaclitaxelCCS(
7
)
| CisplatinCCNS(
7
)
| - | - | Compatible in Y(
10
)
Paclitaxel is a CCS drug, whereas cisplatin is CCNS, which justifies this infusion sequence.(
7
)
When cisplatin is administered first, paclitaxel clearance is reduced, and myelosuppression is more severe. It has been suggested that this decrease in paclitaxel clearance, after cisplatin, may be due to cytochrome P450 inhibition, which is responsible for paclitaxel metabolism.(
17
)
|
| Docetaxel + pamidronate | DocetaxelCCS(
7
)
| Pamidronate | - | - | Compatible in Y(
10
)
No studies were found on administration order.The recommendation is to administer docetaxel first, considering pamidronate may cause nephrotoxicity, which manifests as nephritic syndrome, kidney function deterioration and renal failure, which could alter docetaxel excretion.(
18
)
|
| FOLFIRI | IrinotecanCCS(
7
) + Folinic acid(60 minutes prior) | FluorouracilCCS(
7
) (bolus) | FluorouracilCCS(
7
) (continuous infusion – 46 hours) | - | Incompatible in Y (irinotecan – fluorouracil)(
10
)
Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing the efficacy and cytotoxicity of the latter.(
19
,
20
)
Moreover, for better action of folinic acid, a minimum 60-minute period is required for drug distribution and intracellular metabolism.(
5
)
We observed a synergistic effect when there was previous exposure to irinotecan, intensifying fluorouracil-induced DNA damage.(
21
) According to a study by Falcone et al., toxicity was affected by the administration sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(
22
)
To provide faster patient care, the concomitant initial infusion of irinotecan and folinic acid was proposed, followed by fluorouracil in bolus and fluorouracil in continuous infusion.(
8
)
It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. |
| FOLFOXIRI | IrinotecanCCS(
7
)
| OxaliplatinCCNS(
7
)
+Folinic acid(60 minutes prior) | FluorouracilCCS(
7
)
(continuous infusion–46 hours) | - | Incompatible in Y (irinotecan – fluorouracil)(
10
)
Not tested in Y (fluorouracil – oxaliplatin)(
10
)
Irinotecan in a prodrug and thus requires hepatic microsomal activation. Therefore, whenever possible, this type of drug should be prioritized in multiple infusions.(
5
)
Also, some studies demonstrated there may be an increase in cholinergic side effects of irinotecan when administered after oxaliplatin.(
23
)
Dodds et al., observed the cholinergic effects of irinotecan are manifested by inhibiting acetylcholinesterase.(
24
) Similarly to other alkylating agents, oxaliplatin can also inhibit this enzyme, which can potentiate the cholinergic effects of irinotecan.Regarding the combination between oxaliplatin and fluorouracil, Qin et al. observed in vitro synergistic effect, i.e., apoptosis was more prominent when cells were treated with oxaliplatin first and then with fluorouracil.(
25
) Furthermore, some studies demonstrated oxaliplatin can inhibit the main enzyme of fluorouracil metabolism(dihydropyrimidine dehydrogenase).(
26
)
A synergistic effect was observed when there was previous exposure to irinotecan, intensifying DNA damage induced by fluorouracil.(
21
) According to a study by Falcone et al., toxicity was affected by the administering sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(
22
)
Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing efficacy and cytotoxicity of the latter.(
19
,
20
) Moreover, for better action of folinic acid, a minimum 60-minute period is required for the distribution of the drug and intracellular metabolism.(
5
)
It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. |
| FLOX/B-FOL | OxaliplatinCCNS(
7
)
| Folinic acid(60 minutes prior) | FluorouracilCCS(
7
)
| - | Not tested in Y (fluorouracil – oxaliplatin).(
10
)
Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing efficacy and cytotoxicity of the latter.(
19
,
20
)
Moreover, for better action of folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(
5
)
Regarding the combination between oxaliplatin and fluorouracil, Qin et al. observed in vitro synergistic effect, i.e., apoptosis was more prominent when cells were treated with oxaliplatin first and then with fluorouracil.(
25
) Furthermore, some studies demonstrated that oxaliplatin can inhibit the main enzyme of fluorouracil metabolism (dihydropyrimidine dehydrogenase).(
26
)
|
| FOLFOX | OxaliplatinCCNS(
7
)
+Folinic acid(60 minutes prior) | FluorouracilCCS(
7
) (bolus) | FluorouracilCCS(
7
) (continuous infusion – 46 hours) | | Not tested in Y (fluorouracil – oxaliplatin).(
10
)
Folinic acid stabilizes thymidylate synthase when administered before 5-FU, increasing the efficacy and cytotoxicity of the latter.(
19
,
20
)
Moreover, for better action of the folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(
5
)
Regarding the combination between oxaliplatin and 5-FU, Qin et al., observed in vitro synergistic effect; apoptosis was more prominent when cells were treated with oxaliplatin first and then with 5-FU.(
25
)
Furthermore, some studies demonstrated oxaliplatin can inhibit the main enzyme of 5-FU metabolism (dihydropyrimidine dehydrogenase).(
26
)
To provide more efficient patient care, concomitant initial infusion of oxaliplatin and folinic acid was proposed, followed by fluorouracil in bolus and fluorouracil in continuous infusion.(
27
)
|
| IFL | IrinotecanCCS(
7
)
| Folinic acid(60 minutes prior) | FluorouracilCCS(
7
)
| - | Incompatible in Y (irinotecan – fluorouracil).(
10
)
Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing the efficacy and cytotoxicity of the latter.(
19
,
20
)
Moreover, for better action of the folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(
5
)
A synergistic effect was observed when there was previous exposure to irinotecan, intensifying DNA damage induced by fluorouracil.(
24
)
According to a study by Falcone et al., toxicity was affected by the administering sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(
22
)
It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. |
| MAYO/ McDonald/ fluorouracil + folinic acid | Folinic acid(60 minutes prior) | FluorouracilCCS(
7
)
| - | - | Compatible in Y(
10
)
Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing the efficacy and cytotoxicity of the latter.(
19
,
20
) Moreover, for better action of the folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(
5
)
|
| Paclitaxel + zoledronic acid | PaclitaxelCCS(
7
)
| Zoledronic acid | - | - | Compatible in Y(
10
)
Increase of synergistic effects due to increased apoptosis.(
28
)
|
| Paclitaxel + pamidronate | PaclitaxelCCS(
7
)
| Pamidronate | - | - | Compatible in Y(
10
)
No studies were found describing an administration sequence. The recommendation is to administer paclitaxel first, considering pamidronate can cause nephrotoxicity, which manifests as nephritic syndrome, kidney function deterioration and renal failure, which could alter paclitaxel excretion.(
18
)
|
| TC | DocetaxelCCS(
7
)
| CyclophosphamideCCNS(
7
)
| - | - | Compatible in Y(
10
)
Docetaxel is a CCS drug, while cyclophosphamide is a CCNS drug, which justifies this infusion sequence.Cyclophosphamide is a prodrug, catalyzed directly through cytochrome P450.(
11
) Docetaxel is also oxidated by cytochrome P450 enzymes, especially by CYP3A4 in the liver.(
29
)
We found a few controversial studies that relate ifosfamide and docetaxel because ifosfamide and cyclophosphamide are similar.(
30
)
Schijvers et al. observed the AUC of ifosfomide and its metabolites were smaller when docetaxel was administered first.(
31
)
A study by Ando et al., suggests that docetaxel can competitively inhibit the biotransformation of the prodrug ifosfamide through the isoenzyme CYP3A4 of cytochrome P450.(
32
) However, the studies we found present no clear evidence for an administration sequence of these drugs. |
| Trastuzumab + paclitaxel | Trastuzumab | PaclitaxelCCS(
7
)
| - | - | Compatible in Y(
10
)
Lee et al., observed pre-treatment with trastuzumab resulted in better sensitization of breast cancer cells, i.e., trastuzumab followed by paclitaxel increased the activation and induction of programmed cell death or cell apoptosis.(
33
)
Moreover, due to the possible infusion reaction of the monoclonal antibody, it is recommended that trastuzumab be infused first.(
34
,
35
)
|