Continuing Education Activity

Folinic acid is a medication used in the treatment of various cancers in combination with 5-FU. It is also commonly used as an antidote to folic acid antagonists such as methotrexate. Folinic acid (leucovorin) is an antidote, chemotherapy modulating agent, and rescue agent for the chemotherapy class of medications. This activity outlines the indications, mechanism of action, and contraindications for folinic acid as a valuable agent in the management of certain types of cancer as well as megaloblastic anemia. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, monitoring) pertinent for members of the interprofessional team in the care of patients treated with 5-FU and methotrexate.

Objectives:

• Summarize why it is essential to counsel patients on the risk of developing gastrointestinal toxicity.
• Explain why it is crucial to rule out pernicious anemia or vitamin B12 deficiency in patients before initiating folinic acid therapy.
• Describe why methotrexate levels require close monitoring.
• Outline the importance of interprofessional team members in providing adequate and clear communication between oncology and team members, including nurses and pharmacists, in the setting of chemotherapy.

Indications

Folinic acid (5-formyltetrahydrofolate ([R, S]5-CHOFH4)) is a naturally occurring, reduced form of folic acid commonly known in clinical practice as leucovorin. Often, clinicians use the terms folic acid and folinic acid interchangeably, but they are, in fact, not the same. Folic acid is a synthetic, oxidized, and water-soluble form of folate (vitamin B9) that is used therapeutically and does not exist in nature, whereas folinic acid exists naturally and is biologically active.[1] Both compounds are classified under the general family of “folates” and are dietary supplements to vitamin B9 found in foods such as leafy green vegetables.[1]

Folate supplementation indications include preventing several diseases, such as ulcerative colitis, neural tube defects, and cognitive dysfunction in the elderly.[1] Folinic acid represents over 90% of functional folate derivatives in plasma, and as such therapeutic uses of folinic acid have become important in modern clinical practice, especially because humans cannot synthesize folates de novo.[1] Clinicians can consider folinic acid supplementation superior to folic acid supplementation because folinic acid can reach higher concentrations in plasma, and it can function in the face of defective folate metabolism.[1]

There are several FDA and non-FDA-approved indications of folinic acid. It is most famously known for its use as an antidote for the toxic effects of methotrexate and its use in conjunction with 5-fluorouracil (5-FU), both of which are FDA-approved indications.[2]

Increased levels of folinic acid potentiate the cytotoxic effects of 5-FU in the cell.[3] This finding has revolutionized the treatment of several cancers, most notably colorectal cancer,[4] which represents the second leading cause of death secondary to malignancies.[1] The combination of folinic acid with 5-FU is an FDA-approved indication for the palliative treatment of colorectal cancer. Specifically, patients with advanced, nonresectable adenocarcinoma of the colon, receiving treatment with folinic acid and 5-FU, display more prolonged progression-free survival and response rates.[3] High-dose folinic acid/5-FU regimens can be used as adjuvant therapy for resectable colorectal cancer as well. Folinic acid aids in producing a significant increase in disease-free survival compared to patients that receive treatment with surgical resection alone.[5]

As a derivative of folic acid, folinic acid is useful as an antidote to folic acid antagonists (i.e., methotrexate and pyrimethamine).[6] Frequently referred to as “leucovorin rescue,” folinic acid is used to counteract the toxic effects of high-dose methotrexate therapy.[6] Methotrexate has a variety of indications in the treatment of various malignancies and immunologic disorders. Thus, all such indications requiring methotrexate, especially in high dosages, benefit from folinic acid as rescue therapy.[6] As an antidote, folinic acid functions to limit myelosuppression, gastrointestinal toxicity, nephrotoxicity, and neurotoxicity that can result secondary to high dosages of methotrexate and other folic acid antagonists.[6] Studies show that the administration of folinic acid after weekly doses of methotrexate reduces the incidence of transaminitis (hepatic damage), gastrointestinal complications, and stomatitis (oral ulcers).[7] The inclusion of folinic acid with methotrexate therapy is so essential that chemotherapy protocols using methotrexate also include detailed recommendations regarding folinic acid rescue administration.[6] For diminishing toxicity and counteracting the effects of high-dose methotrexate, folinic acid is FDA approved in both adults and children.

The intravenous formulation of folinic acid (leucovorin calcium) is also FDA-approved for use in adults and children (recommendation IIa, strength of evidence category B) to treat megaloblastic anemia in patients who have normal vitamin B12 levels and in whom oral therapy is not possible.[8]

The list of non-FDA approved indications of folinic acid are far more extensive and include the following:  

• Similar to its use in colorectal cancer, folinic acid has also been shown to potentiate the effects of 5-FU in the treatment of breast carcinoma. This regimen is currently non-FDA approved, partly because there is insufficient evidence that folinic acid can increase the therapeutic index of 5-FU in breast cancer and because many such clinical trials are presently ongoing.[8]

• Regimens including folinic acid and 5-FU also have non-FDA-approved indications for the treatment of unresectable/advanced gallbladder and biliary tree carcinoma,[9] gastric cancer,[10] squamous cell carcinoma of the head and neck,[11] and resectable pancreatic cancer.[12]

• Combination chemotherapy regimens that include folinic acid have been effective in various non-Hodgkin lymphomas. Methotrexate and rescue folinic acid, in conjunction with other chemotherapy agents (i.e., doxorubicin, cyclophosphamide), have shown a complete response rate of 84% in the treatment of diffuse large cell lymphoma.[13]

• For patients who require prophylactic therapy for toxoplasmosis and who are unable to tolerate sulfamethoxazole/trimethoprim, folinic acid is the recommendation in combination with clindamycin and pyrimethamine as an alternative. Folinic acid, in conjunction with pyrimethamine and sulfadoxine, is another option.[14]

• For patients requiring prophylactic treatment for Pneumocystis jirovecii pneumonia and who cannot tolerate sulfamethoxazole/trimethoprim, an alternative treatment can be used that includes folinic acid in combination with pyrimethamine and dapsone, among other combinations.[15]

• Serum plasma levels of homocysteine and folate derivatives have an inverse relationship.[1] In particular, the methionine cycle, which uses homocysteine as a substrate, is highly sensitive to folate deficiency.[1] Thus, when cells have functional depletion of folinic acid, plasma homocysteine levels are markedly increased.[1] In patients with hyperhomocysteinemia, folinic acid has been found to reduce the plasma level of homocysteine, particularly in patients on hemodialysis.[16] This finding suggests that folinic acid intake may reduce the risk of cardiovascular disease. Furthermore, folinic acid levels can be an indirect indicator of homocysteine levels.[1]

• There is evidence that patients who have repeated exposures to nitrous oxide or require treatment with long-term nitrous oxide may benefit from folinic acid prophylaxis to prevent bone marrow suppression.[17]

Mechanism of Action

Folates and folic acid are not biologically active and must be converted into tetrahydrofolate through dihydrofolate reductase. Folinic acid does not require dihydrofolate reductase for conversion into tetrahydrofolate.[1] Tetrahydrofolate and its derivatives then participate in thymidylate and purine synthesis as they are essential in carrying out one-carbon transfer reactions in vivo.[18] These reactions are especially important in the generation of nucleic acids, the regulation of gene expression, and the overall stability of the genome.[1][18] The metabolism of serine, methionine, histidine, and glycine also depends on such substrates and reactions. Thus, folinic acid ultimately plays a crucial role in normal metabolism and gene regulation.[1] Furthermore, folinic acid is essential for synthesizing methionine from homocysteine, as this is a methylation reaction.[1]

The two main roles of folinic acid in pharmacology are to counteract the effects of folic acid antagonists and to enhance the effects of fluoropyrimidines.[19] The former function becomes possible because folinic acid can enter cells through the reduced folate carrier and subsequently be converted to tetrahydrofolate despite the presence of methotrexate, thereby “rescuing” these cells from methotrexate toxicity.[6]

Most folic acid antagonists share a similar mechanism of action that includes the inhibition of dihydrofolate reductase: the enzyme responsible for generating the functional tetrahydrofolate molecule. As mentioned earlier, folinic acid does not require dihydrofolate reductase to convert into its functional derivatives. In this setting, folinic acid functions as an antidote by rescuing these cells from the chemotherapeutic toxicities of folate antagonists such as methotrexate.[18]

While counteracting the side effects of methotrexate, folinic acid functions to enhance the effects of 5-FU. In the cell, 5-FU converts to fluoro-deoxy uridylic acid, a molecule that functions to inhibit thymidylate synthase. Thymidylate synthase is an enzyme that is important in DNA repair and replication. The functional derivative of folinic acid, 5,10 methylenetetrahydrofolate, stabilizes the bound fluoro-deoxy uridylic acid to thymidylate synthase. This interaction yields a ternary complex known as the thymidylate synthase 5-fluorodeoxyuridine monophosphate-methylenetetrahydrofolate complex, which ultimately functions to inhibit thymidylate synthase. Increased cellular amounts of functional folinic acid derivatives lead to increased stability of the aforementioned inhibitory complex, which leads to a depletion of thymidylate synthesis and disrupts DNA synthesis and repair.[19][2]

Administration

Due to the wide range of folinic acid indications and administration guidelines, specific protocols are available that clinicians should follow. In general, folinic acid is compounded with calcium in the form of leucovorin calcium (especially for FDA-approved indications) and can be administered intramuscularly, intravenously, or orally.  The timing, dosage, and route of folinic acid administration depend on the desired outcome for the desired indication.[19]

Adult

• As an antidote for the toxic effects of methotrexate, folinic acid should not be administered concurrently. Most commonly, folinic acid is initiated 24 hours after starting methotrexate therapy. Furthermore, the toxic effects of methotrexate may not be reversible without the initiation of folinic acid within approximately 40 hours of methotrexate. As rescue therapy, folinic acid is generally administered orally, intramuscularly, or as an IV bolus.[6]

• For combination therapy with 5-FU, clinicians should follow specific administration schedules as individual protocols vary. In general, when used for combination therapy, folinic acid is administered as an IV bolus or short IV infusions (minutes-hours).[2]

Pediatric

• Folinic acid usually gets compounded with calcium, and as such, it should not be administered intravenously at rates over 160mg/min. Folinic acid is also not to be administered intrathecally.[20] As with adult dosing recommendations, individual protocols require close adherence, as guidelines differ depending on the desired outcome and particular indication. However, there are similar generalities in both patient populations. For both methotrexate toxicity and combination therapy with 5-FU, the previously mentioned adult administration recommendations remain the same for the pediatric patient population.[2]

Adverse Effects

Because folinic acid administration is usually in combination with chemotherapy agents, it is challenging to discern causative relationships between folinic acid and adverse effects. The most commonly reported adverse reactions to folinic acid include GI upset (nausea, vomiting, diarrhea), leukopenia, alopecia, and stomatitis. Other adverse outcomes include erythema, pruritus, skin rash, and urticaria.[21]

Hypocalcemia can result in patients being treated with folinic acid. Studies suggest that there is evidence of decreased vitamin D levels in such patients, which may contribute to hypocalcemia. Thus, there is a recommendation for calcium monitoring and appropriate supplementation as needed.[22]

Gastrointestinal complications are found to be more frequent and severe, with the addition of folinic acid to 5-FU therapy, particularly in the treatment of colorectal cancer. Patients treated with folinic acid in conjunction with 5-FU were found to have a higher incidence of stomatitis and diarrhea than patients treated with 5-FU alone.  Patients who experience gastrointestinal side effects should not receive further combination treatment until GI toxicity resolves, regardless of severity. It merits noting that patients with GI toxicity, in particular, diarrhea, have the capability of deteriorating rapidly. These patients should be monitored closely, especially older patients or debilitated ones.[23] Elderly patients have the potential to develop severe enterocolitis, diarrhea, and dehydration that may result in death.[24]

Although rare, anaphylactic reactions are possible following the administration of folinic acid.[25]

Contraindications

As mentioned earlier, patients who develop GI toxicity with a combination of 5-FU and folinic acid therapy should no longer receive such treatment until symptoms have resolved.[23]

Intrathecal administration and hypersensitivity to folinic acid or its components are contraindications to its administration.[20]

Caution is necessary for patients receiving folinic acid therapy for the treatment of megaloblastic anemia, particularly in the presence of concurrent vitamin B12 deficiency or pernicious anemia. In such cases, neurologic manifestations may progress and get masked by hematologic remission.[8]

Monitoring

In patients treated for megaloblastic anemia, hematologic monitoring (i.e., complete blood counts) showing improvement generally indicates efficacy.[8]

In patients treated with folinic acid for methotrexate toxicity, it is recommended to monitor serum creatinine and methotrexate levels at 24-hour intervals.[6] A significant decrease in urine output or a significant increase in serum creatinine is considered a sign of a medical emergency in the setting of high-dose methotrexate therapy. Aggressive monitoring of methotrexate levels, early recognition of delayed methotrexate excretion, and prompt administration of folinic acid rescue therapy are imperative in reducing morbidity and mortality in such patients.[6]

When used in combination with 5-FU, the recommendation is that providers monitor complete blood counts (with differential), liver function tests, and electrolytes. Patients who develop diarrhea should be monitored closely until resolution. The renal function requires monitoring in elderly patients or those with known kidney disease/renal impairment.[23]

Toxicity

Therapeutic dosing of folinic acid varies by indication, and there is no internationally accepted single gold standard regimen.[3] Overdose is rare, and there is limited data available that describe overdose effects. As mentioned above, folinic acid is commonly used in conjunction with other chemotherapy agents, and it is challenging to discern causal relationships. Overdose effects generally appear as an extension of the previously mentioned adverse effects.

The toxic dose of folinic acid is unknown, and there is no reported antidote. However, there are reports that excessive administration of folinic acid can nullify the therapeutic effects of specific chemotherapy agents.[24] As therapeutic doses vary depending on the indication, and because multiple folinic acid-containing regimens can exist for a single indication, appropriate literature and guidelines should be sought and followed closely for individual cases.[6]

Enhancing Healthcare Team Outcomes

Managing drug overdose and toxicities relative to chemotherapy regimens requires an interprofessional team of healthcare professionals, including nurses, laboratory technologists, pharmacists, and several clinicians in different specialties. Without proper management, the morbidity and mortality from these regimens (i.e., methotrexate, 5-FU) would significantly increase. Careful monitoring of gastrointestinal complications by nurses and abnormal lab values by clinicians should prompt a coordinated care effort that includes the following:

• Ordering hematologic studies (CBC with differential) and parameters indicating renal function (BUN, creatinine).
• Monitor the patient for signs and symptoms of neurological decline, gastrointestinal complications such as diarrhea/stomatitis, and anemia.
• Consult with the pharmacist about the use of chemotherapeutic agents with a precise record of timing and dosage.
• Consult with the intensivist about ICU care and monitoring if the patient becomes hemodynamically unstable.

Managing malignancies and immunologic disorders is not a process that stops with the oncologist. Careful monitoring and care from the primary care team and nursing are imperative. A thorough record of drug administration is vital to identify and manage cases of overdose or toxic effects quickly. Nursing will often be at the front line for observing toxic effects and promptly report these to the rest of the clinical team. In addition to dosing and administration, the pharmacists must conduct thorough medication reconciliation and report any concerns to the healthcare team. Only by working as an interprofessional team can these detrimental outcomes be avoided. Several studies over 20 years have outlined the importance of folinic acid in chemotherapy. With many more studies currently ongoing, maintaining an up-to-date approach to patient care is necessary.

Folinic acid therapy requires stringent dosing and administration timing to be effective. This precision necessitates an interprofessional team that includes clinicians (MDs, DOs, PAs, NPs), specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]