As promised, I wanted to follow up my last couple of posts (oxaliplatin and 5-fluorouracil [5-FU]) with a quick discussion on leucovorin calcium, the "FOL" in the FOLFOX regimen that is so commonly given in the outpatient setting. Although leucovorin is not a chemotherapy agent or generally used as a stand-alone drug, it certainly is important. Leucovorin has a specific function, and you should be able to explain its purpose.

Leucovorin is a reduced folinic acid that is used in combination with two chemotherapy drugs in particular, high-dose methotrexate and 5-FU. When leucovorin is given with high-dose methotrexate (typically for treatment of leukemias, lymphomas, and osteosarcoma), it is being used as a chemoprotectant. Methotrexate works by depleting folic acid in cells, which causes cell death. Unfortunately, it does not just target cancer cells. Healthy cells can sustain significant side effects, including myelosuppression (WBC, RBC, Plt), hair loss, mouth sores, diarrhea, and liver, lung, nerve, and kidney damage.

Cue our superhero sidekick. Leucovorin is added to methotrexate treatment as a rescue agent because these regimens would otherwise deliver lethal doses of chemotherapy. Often called "leucovorin rescue," it essentially saves the body from toxicity by providing another source of folic acid to those healthy cells in need over a required two- to three-day period of multiple doses. By starting leucovorin 24 hours after methotrexate is given, the chemotherapy has time to work against the cancer cells causing cell death. Methotrexate levels (lab) will be drawn on a regular basis until they decrease to a specified level considered to be safe to discontinue leucovorin administration. Successful rescue requires rapid elimination of methotrexate through the kidneys, which also depends on an adequate pre- and post-hydration protocol. Doses of leucovorin rescue will be ordered at evenly spaced intervals, and it is critical to administer those on time. Severe immunosuppression and toxicity can occur if doses are missed or not given on time.

On the flip side of a chemoprotectant, this drug can also enhance certain chemotherapy drugs such as 5-FU when treating colorectal and head and neck cancers. If given alone, 5-FU only stays in the body for a short period of time; however, adding leucovorin improves the binding of 5-FU to an enzyme in cancer cells. (Cue superhero music: doo, doo, doo-doo! It's Super 5-FU!) This allows the chemotherapy to stay inside the body longer and have a better opportunity to kill more cancer cells.

This unique complementary drug is available as a pill or can be given as an injection (IV or IM). The dose and route of delivery will vary based on the diagnosis you are treating. When administered with 5-FU, it is given via IV typically over two hours. If giving it as part of the FOLFOX, FOLFIRI, or FOLFIRINOX regimen (FOL stands for folinic acid), it can be administered concurrently with oxaliplatin or irinotecan over two hours to save the patient infusion time.

Although side effects from the drug specifically are rare and extremely mild, remember that it enhances 5-FU and can thereby increase the side effects from that drug, particularly the gastrointestinal symptoms of nausea, mouth sores, and diarrhea. Very rarely, leucovorin can cause allergic reactions such as rash, itching, fever, chills, flushing, hypotension, chest pain, shortness of breath, back pain, and swelling of the face, tongue, and throat. Be sure to instruct your patients to notify you immediately if they experience any of these symptoms during infusion. Functioning as a chemoprotectant when given with methotrexate actually decreases the severity of side effects from its chemo-partner.

Although leucovorin may not be the central star of any treatment, it is a pretty super sidekick with the impressive ability to enhance the effects of one chemotherapy (5-FU) and protect against the toxicity of another (high-dose methotrexate). Hopefully, when you find yourself providing patient education you'll be sure to explain the importance of this, at times, unsung hero.