Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment

Proceedings From a Roundtable Discussion, January 26, 2014, St. Petersburg, Florida

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It has been called care coordination, teamwork, integrative care, multidisciplinary treatment, and continuity of care. Regardless of its many monikers, it is here to stay in the contemporary world of cancer care. Perhaps the most accurate title is interprofessional collaborative practice. When health-care professionals work together to coordinate the planning, implementation, and evaluation of cancer treatment, patients may receive better, safer care than if these professionals acted individually.

Today’s cancer regimens are complex, and there is a delicate balance between the benefits and side effects of treatments—one that requires keen attention by all members of the health-care team. It is not unusual for many patients being treated for cancer to see a host of health-care professionals, including physicians, advanced practitioners, physician assistants, pharmacists, social workers or navigators, and mental health professionals, among others. Clearly, patients cannot obtain the short- or long-term benefits of treatment if they experience dose-limiting, unmanageable, or intolerable adverse effects of therapies.

The collaborative interprofessional practice approach is optimal to educate patients, as well as all members of the health-care team, regarding potential adverse effects and to implementing strategies to prevent and manage them. One example of the clinical and safety benefits obtainable through collaborative practice is in the use of two older cancer agents, high-dose methotrexate and fluorouracil (5-FU).

“It is amazing that in this era of targeted therapies, both methotrexate and 5-FU still have very important roles in cancer therapy,” Dr. Schwartzberg said. Both agents have a long history in the treatment of cancer, and they are employed in a wide variety of doses and administration schedules. Methotrexate has been used (alone or in combination with other agents) in the treatment of a host of different cancers in several different clinical settings. Similarly, the first intravenous drug approved 50 years ago, 5-FU remains the backbone of many combination curative and palliative therapy regimens.

The National Institutes of Health (NIH) Federal Register reported that of the 275,000 patients in the United States who receive 5-FU annually, about 8,000 (2.9%) will experience a toxic reaction that causes death in approximately 1,300 patients each year.1 Impaired clearance (usually caused by dihydropyrimidine dehydrogenase deficiency) and medication errors are usually responsible for systemic overexposure of 5-FU.1 “It’s rare for patients to have 5-FU [grade 4] toxicity without having dihydropyrimidine dehydrogenase deficiency,” explained Dr. Schwartzberg.

And finally, all members of this health-care team must be familiar with potential risk factors and strategies for preventing serious toxic effects from methotrexate and 5-FU, must be on the same page regarding the assessment and grading of toxicities, and must be informed about newer pharmacologic interventions for safely managing adverse events should they occur.

Indications for Use of Methotrexate and 5-FU

Methotrexate has been used as monotherapy for head and neck cancer, and 5-FU is a key drug in the treatment of advanced colorectal and gastric cancers. Methotrexate was the first drug to demonstrate curative anticancer activity when used alone, and single-agent methotrexate is still a cornerstone of treatment for malignant gestational trophoblastic disease.2 The broad range of antitumor activity of methotrexate is reflected in the large number of malignant diseases for which it is included in treatment regimens. In addition to antiproliferative activity, methotrexate has antiinflammatory and immunomodulating properties, which allows for its use in a wide range of therapeutic indications across multiple specialties.

The adverse-effect profile of methotrexate varies markedly according to dose (i.e., high-, intermediate-, or low-dose). Most clinicians reserve the term “high-dose” methotrexate for doses ≥ 5 g/m2, as are used for central nervous system prophylaxis in patients with leukemia or high-risk lymphoma or in those treated for leptomeningeal metastases, primary central nervous system lymphoma, or osteosarcoma.

High-dose regimens typically deliver methotrexate as a 4- to 36-hour intravenous infusion. Because of the high probability of associated toxicity, leucovorin rescue doses are administered over a 2- to 3-day period after completion of methotrexate to minimize toxic effects. However, research has shown that leucovorin rescue is not always successful after high-dose methotrexate.3

Methotrexate doses of 50 to 500 mg/m2, as used for malignant gestational trophoblastic disease, are considered to be intermediate. In general, patients receiving intermediate doses do not require aggressive hydration or urinary alkalization. Leucovorin rescue is rarely needed after doses of methotrexate ≤ 250 mg/m2, however patients must be monitored for toxicity. Low-dose intravenous methotrexate (< 50 mg/m2) is sometimes used to treat bladder, breast, and desmoid cancers.

The majority of oncologists advocate high-dose methotrexate–based regimens for treatment of primary central nervous system (CNS) non-Hodgkin lymphomas.4 These are rare tumors, now accounting for about 5% of all CNS tumors.5

5-FU is a key anticancer drug that has broad antitumor activity and is synergistic with other anticancer drugs.6,7 In today’s oncology practice, it is often combined with oxaliplatin, irinotecan, and other drugs as a continuous intravenous infusion. These combination therapies are usually first-line treatments of advanced carcinomas of the colon, rectum, breast, stomach, and pancreas.8

When Treatment With Methotrexate and 5-FU Becomes Toxic

Dosing, Mechanism of Action, and Route of Administration

As previously noted, one of the first questions addressed during the roundtable was “What constitutes high-dose therapy?” The answer is not as straightforward as it would seem, in the opinion of the panel. In terms of methotrexate, it is difficult to define a specific dose that would be considered high dose. According to the literature, Dr. Campen added, high doses are ≥ 5 g/m2, with the duration of infusion varying from 0.3 to 24 hours. In Dr. Schwartzberg’s experience in treating patients with aggressive lymphomas or osteosarcomas, high-dose methotrexate is typically >10 g/m2. Although high-dose methotrexate is used in a narrow, clear-cut population, “we are treating at least one or two patients a week with high-dose methotrexate,” Dr. Schwartzberg said.

Although the focus of discussion was on the use of high-dose methotrexate, Drs. Schwartzberg and Campen agreed that even a low or intermediate dose given to a patient who has pleural effusion or ascites can be toxic. Thus, they emphasized the importance of a thorough evaluation for third-space fluids to prevent such toxicity.

It is important for clinicians to be knowledgeable of the pharmacokinetics of methotrexate, as they vary considerably among patients due to an assortment of factors. Among these factors, impaired renal function and concurrent medications may have the greatest impact. The analysis of some methotrexate parameters related to measuring patients’ response to the drug, such as creatinine clearance, the plasma concentration-time curve (AUC), dose, dose intensity, and rate of infusion, may enable clinicians to identify subgroups of patients who may have an increased risk of severe toxicity or may likely experience poor outcomes.9 In addition, sufficient methotrexate elimination may be adversely affected in patients receiving concurrent nonsteroidal antiinflammatory drugs (NSAIDs), benzimidazoles, and sulfonamides (numerous potential methotrexate-drug interactions have been identified, see Table 1).

As for 5-FU, the question of high dose also was debated, as was the delivery system. 5-FU is one of a few drugs for which the qualitative spectrum of toxicity changes dramatically with the route of administration.10 For instance, diverse patterns of toxic effects are seen when bolus schedules are compared with infusional schedules.10 Furthermore, many patients treated with a 5-FU–based regimen have plasma 5-FU levels that are not in the appropriate therapeutic range,11 so about 50% of patients are underdosed and 10% to 20% are overdosed.12

Approximately 85% of 5-FU is converted to inactive metabolites by dihydropyrimidine dehydrogenase, and only 1% to 3% of the original 5-FU dose exerts cytotoxic effects on tumor cells and normal tissues through anabolic actions.13 Dihydropyrimidine dehydrogenase, an enzyme present in the liver, intestinal mucosa, and various other tissues, metabolizes 5-FU to 5,6-dihydro-5-fluorouracil.14

Continuous infusion 5-FU may be administered at higher doses over 2 to 5 days and at lower doses continuously for weeks. A 48-hour infusion of 5-FU is often used in treating patients with colon cancer, said Dr. Schwartzberg, but 3- to 5-day infusions of 5-FU are typically still used for upper gastrointestinal malignancies such as esophageal or gastric cancer. Furthermore, continuous-infusion 5-FU is occasionally used as a radiosensitizer in cases of rectal cancer. Dr. Schwartzberg explained that an oral prodrug of 5-FU (capecitabine) often has replaced those long 5-FU infusions, given similar pharmacokinetics and an easier delivery system.

Considerations in using leucovorin in conjunction with both methotrexate and 5-FU were briefly mentioned during the roundtable discussion. In regard to methotrexate, leucovorin has a clear rescue role (Table 2). Along with hyperhydration and urine alkalization, pharmacokinetically guided leucovorin rescue is a key component in the safe administration of high-dose methotrexate in patients with normal renal function.15 However, in regard to 5-FU, this is not the case. Leucovorin actually potentiates the activity of 5-FU, because both are part of the same metabolic pathway within cells. (Leucovorin rescue is discussed further in the section on Strategies for Prevention and Monitoring; page 9, and in Table 2, page 8.)

Types of Adverse Effects and Toxicities

The panel discussed adverse effects that occur with high-dose methotrexate and 5-FU. According to Dr. Schwartzberg, renal toxicity is one of the biggest concerns with high-dose methotrexate. The reported incidence of acute kidney injury with high-dose methotrexate is 1.8% of patients.15 The rate may be higher among patients with diabetes or those who have poor renal function prior to treatment, added Dr. Campen.

Both the dose and the route of administration of methotrexate and 5-FU play a major role in the occurrence of serious complications in some patients. For example, methotrexate can be given in higher doses over prolonged intravenous infusions, which require supportive care measures to prevent unacceptable toxicity.15,16 As for 5-FU, exposure is influenced by the method of administration, circadian variation, and impaired liver function, accounting for both interpatient and intrapatient variability in 5-FU plasma concentrations during the course of administration.11

Crystal nephropathy may occur when methotrexate and its metabolites precipitate in the renal tubules (Figure 1).15 This initially manifests as asymptomatic elevations in serum creatinine levels but may progress to more severe renal injury and tubular necrosis.15 Impairment in renal clearance of methotrexate causes toxic levels of methotrexate to accumulate, furthering adverse events.15 Another manifestation of methotrexate toxicity is transient elevation of hepatic transaminases, and in severe cases, multi-organ failure.15 Dermatologic reactions, ranging from mild erythematous eruptions to exfoliative dermatitis, may occur in ≤ 10% of patients receiving high-dose methotrexate.15

Both methotrexate and 5-FU may cause neurotoxicity that can vary from brief, transient episodes to more severe, chronic complications; this is related to the route of administration and the cumulative dose.17 Neurotoxic manifestations may include confusional states, cerebellar dysfunction, headache, and spinal cord damage with myelopathy.17 In fact, transient CNS disturbances (such as cortical blindness, hemiparesis, and seizure) have been reported in up to 15% of high-dose methotrexate courses.15 “Nurses must be absolutely alert to the CNS changes in their patients receiving methotrexate,” said Ms. Vogel. “You cannot assume that it is a sleeping pill or an antiemetic that is making them drowsy,” she added, emphasizing the importance of performing frequent neurologic assessments.

Common adverse effects of 5-FU include nausea, vomiting, myelosuppression, and diarrhea,18 which typically occur between 3 and 8 days after 5-FU administration. Other possible adverse events are stomatitis, gastrointestinal (GI) mucosal ulceration, and bleeding.12 These effects may result in dehydration and electrolyte imbalances, as well as enterocolitis, which can progress to systemic infection, sepsis, and even death. “We cannot overemphasize the importance of mouth sores as a potential site of infection,” said Ms. Vogel.

Although symptomatic cardiotoxicity from 5-FU is uncommon (occurring in 1% to 18% of patients),19-20 it can be potentially fatal and thus warrants attention. Some evidence suggests an increased risk for cardiotoxicity with continuous infusion or when 5-FU is administered with cisplatin.21 The most common symptom of cardiotoxicity is chest pain, followed by palpitations, dyspnea, and hypotension.21 More severe events, including myocardial infarction, cardiogenic shock, or cardiac arrest, are reported in up to 2% of patients receiving 5-FU.21

The panel briefly addressed the relationship between the occurrence of adverse effects and the method of 5-FU administration. According to Dr. Schwartzberg, there are differences in toxicity profiles with continuous infusion and bolus delivery. “Specifically, you see a lot more hand-foot syndrome and less myelosuppression with continuous infusion than with intravenous bolus 5-FU,” Dr. Schwartzberg noted. “Continuous infusion 5-FU is associated with more manageable toxicities,” he added.

Another issue of 5-FU administration is the existence of dihydropyrimidine dehydrogenase deficiency, a genetic inability to metabolize dihydropyrimidine dehydrogenase.

Strategies for Prevention and Monitoring

The prevention and monitoring of toxicities associated with methotrexate- and 5-FU–based chemotherapy regimens present a challenge to oncologists and advanced practitioners in oncology. Although therapeutic serum drug monitoring is common for particular antimicrobial and immunosuppressant drugs, it is not yet reliable or easily available in oncology practice. Thus, clinicians must make critical decisions regarding the initiation and continued use of methotrexate and 5-FU through approaches that continue to be debated. For this reason, it is essential that clinicians be armed with appropriate strategies to prevent and manage toxicities when caring for patients treated with either agent.

Prior to Methotrexate Administration

Dr. Schwartzberg emphasized the importance of thoroughly assessing patients’ needs before methotrexate therapy is started. Patients should be screened for adequate bone marrow, hepatic, and renal function. Additionally, a patient’s urinary output should be > 100 mL/h, and his/her urinary pH must be maintained at > 7.0, as crystallization of methotrexate is less likely in an alkaline environment.22 A detailed medication history should be taken to assess for potential drug–drug interactions. Clinicians should be aware that drug elimination may be reduced in patients with renal impairment, ascites, or pleural effusion. A baseline physical examination should be performed before patients begin therapy and should be assessed frequently during therapy.

Important prophylactic interventions are adequate hydration (2.5–3.5 liters of fluid/m2/24 hours), beginning 12 hours before the start of methotrexate infusion and continuing for 24 to 48 hours,15 and urinary alkalization with intravenous sodium bicarbonate, instituted prior to and during methotrexate administration. Patients should be educated about the potential side effects and informed that many of these effects may resolve relative to time and/or treatment interventions.

As previously mentioned, clinicians should be aware of common drug interactions with methotrexate. For instance, concomitant administration of some NSAIDs with high-dose methotrexate may lead to elevated and prolonged serum methotrexate levels, which can result in death secondary to severe hematologic and GI toxicities. Other adverse effects may include malaise, nausea, vomiting, headaches, and mild alopecia, which are typically not life-threatening. Clinicians should review the patient’s current medications prior to starting methotrexate and address any potential problematic drugs.  “[Physicians] depend on our clinical oncology pharmacist to pay attention to potential drug interactions, because it is something that we don’t do routinely,” said Dr. Schwartzberg. “So it’s a great asset to have pharmacists working with us.”

During Methotrexate Administration

As methotrexate is predominately eliminated by the kidneys, assessment of renal function before and during infusion of each dose of high-dose methotrexate is necessary. Key measures of kidney function include serum creatinine, serum potassium (severe renal failure may lead to life-threatening hyperkalemia), serum methotrexate, blood urea nitrogen (BUN), urine output, and urine pH (Table 3).23–25 Plasma methotrexate levels should be monitored closely to detect any delay in methotrexate clearance.26 Depending on the treatment protocol, plasma methotrexate assays may be appropriate at 24, 48, and 72 hours after the start of methotrexate infusion.24 Serum methotrexate levels should be assessed with ongoing adjustment in hydration, alkalization, and leucovorin rescue until the target level (< 0.05–0.1 μmol/L) is reached.27

“I want to teach my nurses about monitoring urine output, what goes in and what comes out, and assessing serum creatinine levels,” stated Ms. Vogel. “Astute oncology nurses also should know when to notify a practitioner,” she added. In addition, Dr. Schwartzberg stressed the significance of watching pH levels. “It is important that the drug is excreted, and so we take this very seriously with high-dose methotrexate—particularly in adults,” said Dr. Schwartzberg. “Kids tend to handle [the treatment] a little better, and they usually have better kidneys [especially]. When you are dealing with adults, you have to be careful.”

Prior to 5-FU Administration

Appropriate preventive measures also should be implemented before patients begin 5-FU monotherapy or combination therapy. As 5-FU is associated with possible cardiotoxicity, prechemotherapy history and physical examination for careful evaluation of cardiovascular risk factors that could be exacerbated by 5-FU are paramount for all patients.28 However, research has yet to provide conclusive evidence regarding the value of prophylactic cardiac agents (i.e., calcium channel blockers and nitrates).29

Though tests are available to determine the relative activity of the dihydropyrimidine dehydrogenase enzyme,30 they do not always predict 5-FU toxicity. “The issue with dihydropyrimidine dehydrogenase deficiency is a little bit confusing,” noted Dr. Schwartzberg. “I have seen grade 3 toxicity occur in patients who do not have dihydropyrimidine dehydrogenase deficiency, and I think it is related to the combination therapy, the degree of prior therapy, and, to some extent, the type of tumor. However, I believe dihydropyrimidine dehydrogenase deficiency testing, like some other pharmacogenetic testing, is underutilized.”

Ms. Vogel shared her experience with dihydropyrimidine dehydrogenase deficiency. “I keep hearing that dihydropyrimidine dehydrogenase deficiency is rare and may not be a factor in affecting outcomes, but it is highly variable in the population. In east Tennessee, I have seen this several times in the past few years in our practice. Of course, in years past, testing was not available.”

During 5-FU Administration

Once 5-FU therapy is started, clinicians should be aware of certain signs and symptoms of possible toxicity. As 5-FU–based therapy is often administered via infusion pumps, clinicians also need to be aware of potential problems associated with malfunction in pump usage.

Infusion errors and pump failures can cause serious harm and even death. According to one report, over a 4-year period, more than 56,000 adverse events and 710 deaths associated with infusion devices were reported to the  U.S. Food and Drug Administration (FDA)—more than for any other medical technology.31 This takes into account only those that were reported. Thus, a thorough education on pump functioning is needed for both health-care professionals and patients.

Typical infusion pump problems include software malfunctioning, alarm errors, inadequate user-interface design, broken components, and battery failures.32 Patients, especially those receiving ambulatory intravenous infusions, should be instructed about symptoms to report to their health-care team. Strategies to prevent problems include having a backup plan in effect in case of an infusion pump failure; labeling the infusion pump channels and/or tubes with the name of the medication or fluid; verifying that the infusion pump is programmed for the right dosage, at the right rate, and the right volume to be infused; obtaining an independent double check of infusion pump settings; and using available resources.32

Strategies for Managing Methotrexate and 5-FU Toxicities

Prevention of serious methotrexate and 5-FU toxicities is clearly the ideal goal. However, when adverse effects do occur, they require prompt identification through accurate grading and knowledge about effective pharmacologic interventions. All members of the health-care team, including physicians, advanced nurse practitioners, and clinical pharmacists, need to have a firm grasp on the myriad challenges involved while working collaboratively to safely manage patients with these potentially life-threatening complications.

Grading Toxicity

The panel discussed the difficulty of accurately grading adverse effects of methotrexate and 5-FU (such as diarrhea, neuropathy, mucositis, and skin complications). According to Dr. Schwartzberg, grading may be highly variable from one particular type of toxicity to another depending on whether the Eastern Cooperative Oncology Group (ECOG) grading scale or the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) is used. Because of this subjectivity, “One person’s grade 1 can be another person’s grade 3,” said Dr. Schwartzberg. The panel agreed that these toxicity grading scales should be used as a framework, and improvements in standardizing vocabulary and educating staff members are needed.

The panel noted the importance of descriptive documentation rather than general levels of severity. For example, “whether an adverse effect is mild, moderate, or severe may be completely in the eye of the beholder,” said Dr. Schwartzberg, discouraging the use of these adjectives. Dr. Campen agreed, noting that “severe” 5-FU–induced diarrhea can mean something different to each patient. Rather, Dr. Campen suggested that a more objective method of grading the severity of diarrhea would be to describe the number and duration of diarrheal episodes.

Other adverse effects that may be difficult to grade are mucositis and cutaneous toxicity, even when a patient is receiving 5-FU in the setting of a clinical trial. Team members may need focused education to describe clinical observations to a patient experiencing mucositis. Cutaneous toxicity may occur with both methotrexate and 5-FU, added Dr. Schwartzberg, and it may be a challenge for health-care practitioners who are not dermatologists to describe such skin complications in a way that is meaningful to others.

Methotrexate Nephrotoxicity: Glucarpidase

Key steps to preventing methotrexate-induced nephrotoxicity center on leucovorin rescue, urine alkalization, and hydration.33 Although the majority of patients benefit from this standard approach, others experience prolonged, elevated plasma methotrexate concentrations and nephrotoxicity. For these patients, the carboxypeptidase enzyme glucarpidase is an effective therapy approach.34

Glucarpidase, a recombinant bacterial enzyme, hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classic antifolates, such as methotrexate.35 Glucarpidase converts methotrexate to its inactive metabolites, 4-deoxy-4-amino-N10-methylpteroic acid and glutamate, and provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.

Glucarpidase has been available since 1993 through the FDA’s compassionate-use criteria.33 The drug was formally approved by the FDA in January 2012 for the treatment of toxic plasma methotrexate concentrations (> 1 ìmol/L) in patients with delayed methotrexate clearance due to impaired renal function.35 Patients may be candidates for glucarpidase treatment if they have extremely high methotrexate levels, often accompanied by renal dysfunction. “You are trying to prevent the rare side effects such as neurotoxicity and seizures,” noted Dr. Campen. Other potential candidates for glucarpidase may include those with markedly increased serum creatinine levels, CNS changes (such as problems with speech, vision, or mental function), and extreme weakness/fatigue.35

Clinical studies have shown glucarpidase rapidly reduces plasma methotrexate concentrations (Figure 2).36,37 In a recent study by Widemann and colleagues,37 476 patients who developed renal toxicity and delayed methotrexate elimination from treatment for osteosarcoma, non-Hodgkin lymphoma, or acute lymphoblastic leukemia were given intravenous glucarpidase. The result was a 99% or greater sustained reduction in serum methotrexate levels within the first through the last measurements (15 minutes to 40 hours).

The question of when to administer glucarpidase has been addressed in the literature, as well as by the panel. Widemann and colleagues found that early intervention with the combination of glucarpidase and leucovorin was highly effective in patients with high-dose methotrexate-induced renal dysfunction.36 However, they noted that severe toxicity and mortality occurred when glucarpidase was administered > 96 hours after the start of methotrexate infusion.36 According to Dr. Campen, even after 48 hours of elevated serum levels of methotrexate, glucarpidase may be a better option than dialysis or higher doses of leucovorin.

No major adverse effects have been reported with glucarpidase.33 In nearly 300 study patients, the most common side effects were paresthesia, flushing, and nausea/vomiting (all 2%).22,35 “Glucarpidase appears to have little toxicity,” noted Dr. Schwartzberg. “Given the profound and life-threatening effects of methotrexate overdose, I would have a low threshold to use it, even if a patient was on the borderline of a toxic dose.” Dr. Campen agreed: “If you have already maximized the dose of leucovorin and have not seen patient benefit, you need to think of glucarpidase right away.”

In fact, the National Comprehensive Cancer Network (NCCN) Guidelines for both CNS lymphomas and non-Hodgkin lymphoma now include glucarpidase.31,35 For patients with CNS lymphomas who have delayed methotrexate excretion and high plasma methotrexate concentrations, the NCCN guideline notes that early intervention with glucarpidase has demonstrated efficacy in rapidly reducing these high methotrexate plasma concentrations and preventing severe toxicity39 and should be considered over hemodialysis. Under the supportive care section of the NCCN Non-Hodgkin Lymphoma Guidelines,38 the NCCN panel recommends considering the use of glucarpidase if a patient has significant renal dysfunction and methotrexate levels > 10 ìmol beyond 42 to 48 hours.

Nurses must be knowledgeable in glucarpidase administration along with leucovorin and precautions with its use (Table 4). According to Dr. Campen, glucarpidase is typically given in a single intravenous injection (50 U/kg)35 and begins working almost immediately. Glucarpidase reduces methotrexate levels in the bloodstream but has no effect on intracellular methotrexate levels. Therefore, leucovorin, which combats intracellular methotrexate, is a necessary component of treatment.38

The optimal timing of leucovorin rescue after high-dose methotrexate is a topic of debate. A 2014 study by Cohen and Wolff 40 found that leucovorin rescue begun 30 to 36 hours after the start of methotrexate was safe, whereas leucovorin rescue at 42 to 48 hours resulted in toxicity. Thus, they concluded that leucovorin rescue should be started no later than 36 hours after the start of methotrexate treatment.

According to the NCCN Guidelines for non-Hodgkin lymphoma,38 leucovorin rescue should be continued for at least 2 days after the administration of glucarpidase and should be continued until the patient’s methotrexate plasma concentration has been maintained below the leucovorin treatment threshold for at least 3 days.35 However, leucovorin should not be administered within 2 hours before or after glucarpidase,36 as coadministration of these agents diminishes their effectiveness. In addition, nurses should continue with hydration and alkalization of urine, according to the physician’s recommendations.35

Thymidine in Managing Methotrexate Toxicity

The use of thymidine in the treatment of methotrexate toxicity has also received attention in the literature and by the panel. Thought to be an attractive complement to glucarpidase and leucovorin, thymidine reportedly prevents methotrexate toxicity in patients with normal renal function and does not compete with metheotrexate for transport into cells.15

Originally studied in the late 1990s, the addition of thymidine to glucarpidase and leucovorin was the focus of a recent study by Widemann and colleagues.36 They concluded that the combination of glucarpidase and leucovorin was an effective option. Severe toxicity and mortality occurred despite thymidine administration. Dr. Schwartzberg did not endorse the use of thymidine in the management of methotrexate toxicity. “I don’t believe [thymidine] provides much benefit, and there is not a lot of literature to support its use,” he stated.

Resumption of High-Dose Methotrexate

Many cancer patients require multiple courses of high-dose methotrexate, and the delay or omission of these courses may adversely affect their prognosis.41,42 The panel questioned whether it is safe to resume high-dose methotrexate after acute kidney injury and glucarpidase use. According to a small study by Christensen and colleagues,41 an anecdotal report,42 and the view of the panel, the answer appears to be yes. “After the rescue, if the patient’s renal toxicity resolves completely and the need is still there (which it usually is), you can resume high-dose methotrexate cautiously,” stated Dr. Schwartzberg. “Most cases of renal dysfunction are short-lived,” added Dr. Campen.

In the study by Christensen and others, 20 pediatric cancer patients received glucarpidase, and 13 of them received 39 courses of high-dose methotrexate afterward.41 The investigators found that 11 of the 13 patients tolerated the rechallenge of high-dose methotrexate therapy well. During treatment courses that necessitated glucarpidase, the median time to complete methotrexate excretion was 355 hours during the first course; 90 hours for the next course; and 72 hours for subsequent courses. Although one patient experienced nephrotoxicity upon resumption of treatment, renal function returned to baseline in all patients, and no patients died as a result of methotrexate-induced nephrotoxicity. 

Overexposure to 5-FU: Uridine Triacetate

There is no FDA‒approved antidote for 5-FU overexposure. However, successful results have been reported with the use of the investigational drug uridine triacetate (formerly known as vistonuridine).43–45 This is an oral bioavailable prodrug of uridine, a direct biochemical antagonist of 5-FU toxicity.43 After conversion of uridine triacetate to uridine, it reduces incorporation of 5-FU metabolites, particularly into noncancerous cells.46

Although not yet approved in the United States, uridine triacetate is available under the expanded access protocol and in the European Union on a named patient supply basis46 (see the section on “Expanded Access Programs,” on page 16 and the sidebar “Questions Answered About Uridine Triacetate,” on page 14). Other potential applications of uridine triacetate under study are for treatment of neurodegenerative and mitochondrial disorders46 and combination use with high-dose 5-FU, which may enable repeated tumor exposure to unprecedented levels of intact 5-FU that enhance antitumor efficacy.

Current candidates for treatment with uridine triacetate include those who have 5-FU overexposure due to a dosing error, pump malfunction, or error in programming an infusion pump. Patients with partial or total dihydropyrimidine dehydrogenase deficiency, for whom its accumulation may be potentially lethal, may also be candidates for treatment with uridine triacetate.

According to Drs. Campen and Schwartzberg, other core patients for whom uridine triacetate should be considered are those with very early onset 5-FU toxicity and individuals with a history of severe 5-FU toxicity. “Patients who would benefit are the ones who call 2 or 3 days after they’ve had their infusion and report mouth sores, fever, diarrhea, and rash,” according to Dr. Schwartzberg.

Early onset toxicity should also be a red flag for nurses. Ms. Vogel emphasized the need to educate nurses, particularly those handling the triage phone calls, that the mouth sores shortly after receiving 5-FU are not the same as the mouth sores that occur a week after treatment with combination cyclophosphamide and doxorubicin. “Nurses need to know when to expect it, and when to bring that patient in,” added Ms. Vogel. Finally, uridine triacetate could be considered for their future courses of 5-FU, as noted by Dr. Campen. 

Uridine triacetate has demonstrated effectiveness for patients with emergency 5-FU overdose, as well as for those with known or suspected overexposure to 5-FU that occurs because of dihydropyrimidine dehydrogenase deficiency. In addition, there was an anecdotal report of a patient with colon cancer experiencing 5-FU overdose that was successfully treated with a 5-day course of oral uridine triacetate.45

An update on clinical experience with uridine triacetate in 98 patients with 5-FU overexposure was presented at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO).44  These patients received uridine triacetate, and 96 (98%) recovered fully. Patients also experienced reduced or absent GI, hematologic, and other toxicities of overexposure to 5-FU. Adverse events related to uridine triacetate are reported as mild and infrequent.44

Overexposure to Capecitabine: Uridine Triacetate

Oral capecitabine use has increased over the years, noted Dr. Campen. It is a prodrug that is enzymatically converted to 5-FU preferentially in tumor cells, which improves its therapeutic ratio, Dr. Schwartzberg added. However, in the setting of severe dihydropyrimidine dehydrogenase deficiency, it is possible to experience life-threatening toxicity from capecitabine.

If a patient develops capecitabine overdose, uridine triacetate is an appropriate option through the expanded access program to prevent severe morbidity or even death, Dr. Campen said. He noted that unlike 5-FU infusions, which are given over 48 hours, capecitabine is given orally, twice daily, for 14 days of a 21-day cycle. Thus, by day 14, toxicities are already present. Therefore, if a patient had grade 4 toxicity during the capecitabine cycle, uridine triacetate is not an option.

Final Thoughts on Uridine Triacetate

The panel recommended steps to be taken by the health-care team while awaiting the arrival of uridine triacetate. First, the patient should definitely be admitted to the hospital, Dr. Campen said. Then, each of the patient’s symptoms should be optimally treated, Dr. Schwartzberg continued. For instance, diarrhea should be treated by institutional protocols, and good mouth and skin care is needed. If the patient has become neutropenic, pan-cultures should be done, and in some cases, prophylactic antibiotics should be started, added Dr. Schwartzberg.

Finally, the panel stressed the importance of developing and implementing triage plans and protocols for monitoring patients on high-dose methotrexate (Table 5) and 5-FU. All members of the panel considered protocols essential for making prompt decisions regarding pharmacologic management, such as treatment with glucarpidase and uridine triacetate. These agents are rarely used, so clear instructions should be posted on both inpatient and outpatient areas of clinical oncology sites. In these cases, preparedness is critical, as every minute counts when obtaining these two drugs and securing informed consent, said Dr. Schwartzberg.

Protocols for glucarpidase use may vary, but most generally follow approved use from the package insert35 and note specific inclusion criteria, said Dr. Campen. Protocols should be in place to guide the acquisition of uridine triacetate, which would include contact information of the local investigational review board and the pharmaceutical company.

Expanded Access Programs

The FDA’s expanded access program is a means by which manufacturers make investigational new drugs available, under certain circumstances, to treat patients with a serious disease or condition and who cannot participate in a controlled clinical trial. There is a process to obtain and administer a drug through the expanded access program (see sidebar on “Learning More About Expanded Access Programs,” above).

Use of the expanded access program has increased dramatically in recent years. In 2010, 1,000 patients received treatment via the expanded access program. A year later, that number had increased by 20% to 1,200.47

Requirements and Benefits

The basic requirements for a pharmaceutical agent to be accepted into the expanded access program follow:

  • There is no comparable or satisfactory alternative therapy for a condition.
  • The potential benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease or condition being treated.
  • The use of the drug will not interfere with or compromise its further development for clinical investigation.48

The benefits associated with expanded access programs include48:

  • Providing access to drugs for patients with serious or life-threatening diseases without alternative therapies (outside a clinical trial) and who are to accept possible greater risks.
  • May provide patients with a measure of autonomy in their health-care decisions.
  • This use of a new drug can help bridge the gap between the latter stages of product development and approval by making a drug widely available during that gap period.
  • Expanded access use of an investigational agent may help foster development of additional uses of a drug (e.g., from anecdotal evidence of benefit in a disease other than that being studied).

Clinicians must be careful not to provide a sense of false hope that a particular patient may be able to receive further treatment via the expanded access program. The drug manufacturer and the patient’s doctor must make special arrangements to obtain the drug for the patient. Clinicians also need to make patients aware that drug companies are not required to make their drug available through the expanded access program or to make more of a drug for that purpose.49

Concerns and Costs

There are risks and concerns regarding expanded access programs.49 For instance, some serious safety issues may not become apparent until post marketing. In addition, early access to investigational therapies could make phase II and III clinical trials more difficult to perform. Also, from the standpoint of the drug manufacturer, the manufacturing capacity is often limited in early phases, and thus the supply of the drug for expanded access could limit the supply needed for clinical trials.

From the patient perspective, health insurers may not reimburse substantial costs associated with the drugs. From the physician perspective, the costs to provide access may not be fully compensated; in addition, physicians may face liability issues, and their participation requires commitment (i.e., contacting the drug manufacturer and filing paperwork).49

Investigational New Drug vs Drug in the Expanded  Access Program

Health-care professionals should be cognizant of the difference between an investigational new drug (IND) and a drug in the expanded access program. The main distinction is that expanded access users (patients and physicians) are not required to provide information about the safety or effectiveness of the drug. In addition, to authorize the expanded access use, the FDA must determine that the patient has a serious or life-threatening disease or condition and that no other comparable or satisfactory therapeutic options are available. Moreover, the FDA cannot compel a drug manufacturer or marketer to provide expanded access to its drug, which is voluntary on the part of a company.49

Steps to Obtaining a Drug Via the Expanded Access Program

There are steps if a clinician wants to obtain a drug via the expanded access program. First, he or she should ensure that the manufacturer of the unapproved drug is willing to provide the drug. If the manufacturer agrees to provide the drug, the clinician should submit an IND application to the appropriate review division. In an emergency situation, the request to use the drug may be made via telephone or other rapid means of communication, and authorization to ship and use the drug may be given by the FDA official over the telephone. This process is referred to as an emergency IND application. In a nonemergency situation, a written request for individual patient use of an investigational drug must be received by the FDA before shipment of and treatment with the drug may begin.50

To obtain the drug, clinicians also must submit a brief clinical history of the patient, including the diagnosis, the disease status, prior therapy, response to prior therapy, and the rationale for requesting the proposed treatment along with a list of available therapeutic options that would ordinarily be tried before the investigational drug. In addition, clinicians must provide a proposed treatment plan describing the dose, route, planned duration, monitoring procedures, and modifications for toxicity (e.g., dose reduction or treatment delay).50

The Benefits and Barriers of Collaborative Practice

Because prevention of and monitoring for methotrexate-based and 5-FU–based toxicities can be challenging, increasing numbers of health-care professionals are employing collaborative interprofessional approaches to nurture improved patient outcomes. Aggressive monitoring and prompt intervention by clinicians can promote drug excretion, minimize many adverse effects, and allow patients to receive subsequent treatment as appropriate.

Team-based care has been promoted as one essential component for meeting the supply and demand workforce imbalance, as well as a crucial element to improving health-care delivery.53 In oncology, team-based care takes many forms, such as inpatient care management teams or interprofessional disease-oriented care programs.54

Both ASCO and NCCN have embraced the benefits of interprofessional collaborative practice. The ASCO Workforce Strategic Plan recommends educating all oncologists about collaborative practice, including increasing awareness and acceptance of the role of advanced practitioners in oncology practice.55,56 To this end, ASCO offers multidisciplinary cancer management courses in academic and community settings for physicians, nurses, and pathologists and has worked with both the Oncology Nursing Society (ONS) and the American Academy of Physician Assistants (AAPA) to address the educational needs of the oncology care community in the value of collaboration. As for the NCCN, its alliance of leading cancer centers pioneered the concept of interprofessional team approach to patient care,57 and those familiar with its tumor-specific guidelines are aware of the repeated mention of the role of collaborative practice in cancer care. Furthermore, a 2003 Institute of Medicine report recommended that all health-care professionals be educated to deliver care in collaborative models.53

Although there are numerous benefits to promoting and implementing collaborative oncology practice initiatives, there are remaining issues and barriers to implementation. The education of oncology nurses, physician assistants (PAs), and pharmacists varies greatly, and overlapping and complementary roles have not been addressed. In addition, most programs for oncology advanced practice nurses (APNs), including nurse practitioners (NPs) and clinical nurse specialists (CNSs), as well as PA programs have little oncology content. Additionally, licensing and regulation of  APN  and PA practice vary from state to state.

Administrators, managers, and clinicians must work to differentiate and delineate roles designed to maximize productivity in patient care services and in the development of effective communication strategies among team members to reduce duplication and establish effective collaborative practice models.58 It is vital that all oncology collaborative practice team members engage in ongoing self-examination and determine how all team members may best contribute to deliver high-quality and cost-efficient patient care.59

Clinical pharmacists have key roles as well, such as ensuring the accuracy of all drug calculations and assuring the safety of inpatient and ambulatory infusion pumps. The pharmacist can review all of a patient’s medications, including prescription, over the counter (OTC), and supplements, to identify potential drug interactions with chemotherapy agents. In addition, oncology pharmacists may collaborate with physicians regarding dosing changes and contribute important clinical details to therapy protocols. For instance, oncology pharmacists have collaborated with oncologists to decrease the potential for drug–drug reactions in patients with lymphoma receiving methotrexate.60

Advanced practice nurses—NPs and CNSs—are instrumental in educating patients, families, and other care providers involved with particular patients about treatment regimens, potential adverse effects and manifestations, and management strategies. For instance, APNs should teach and reinforce the importance of patient monitoring to staff, clinic, and infusion nurses. For a patient receiving high-dose methotrexate, this would include serum drug levels, urinary output and urine pH, and serum creatinine. Nurses must promptly recognize symptoms suggestive of toxicity, understand the importance of adequate hydration, and administer medications as directed. There are published reports of how oncology clinic nurses successfully collaborate with physicians to monitor and manage patients with methotrexate-induced toxicities.26

 In today’s oncology practice, the roles of PAs, APNs, and oncology pharmacists are expanding to settings such as wellness clinics, survivorship and long-term follow-up clinics, breast health clinics, pain and palliative care services, and other subspecialty areas within cancer care.54 In one instance, a regional Canadian cancer network successfully implemented a program that promotes increased interprofessional collaboration among nurses, physicians, pharmacists, and other health-care providers such as nutritionists and social workers on cancer teams.61


Two important aspects regarding contemporary cancer care were demonstrated at this roundtable discussion, held at the JADPRO Live 2014 educational symposium. First, the discussion among an oncologist, an APN, and a clinical oncology pharmacist provides a clear example of how collaboration actually works, particularly with regard to preventing and managing toxicities associated with administration of high-dose methotrexate or 5-FU. Second, the panel demonstrates the continued importance of increasing and enhancing interprofessional collaborative practice in order to maximize the quality of care given to patients with cancer, whether the goal of therapy is curative or palliative.


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26. Warnick E, Auger D: Management of patients with primary central nervous system lymphoma treated with high-dose methotrexate. Clin J Oncol Nurs 13:177-180, 2009.

27. Widemann BC, Adamson PC: Understanding and managing methotrexate nephrotoxicity. Oncologist 11:694-703, 2006.

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29. Cianci G, Morelli MF, Cannita K, et al: Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity. Br J Cancer 88:1507-1509, 2003.

30. Ciccolini J, Gross E, Dahan L, et al: Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: Hype or hope? Clin Colorectal Cancer 9:224-228, 2010.

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How to Earn Credit

CE is available on May 1, 2014 and expires on May 1, 2015.

A continuing education activity for physicians, physician assistants, nurse practitioners, nurses, pharmacists, and other allied health professionals specializing in the field of oncology.

This activity is supported by an unrestricted...

Collaborative Exchange: Indications and Dosing

Indications and Dosing of Methotrexate and 5-FU

Dr. Campen: The interesting thing about methotrexate is that it has been used for such a long time. You would think there would be a specific dose that would be considered “high dose,” but high dose is actually quite variable. [Dosage] depends on the ...

Collaborative Exchange: Leucovorin and Glucarpidase

The panel discussed the rationale behind the continued use of leucovorin in conjunction with glucarpidase.

Dr. Campen: We continue with leucovorin to provide a full basis for recovery of the cells. One important thing to know is that leucovorin should be given separately from glucarpidase because...

Questions Answered About Uridine Triacetate

Q. What is uridine triacetate?

A. It is an investigational, orally active prodrug of uridine currently under development as an antidote to overexposure of fluorouracil (5-FU). Although not yet approved by the U.S. Food and Drug Administration, it has been shown to be effective in treating patients ...

Collaborative Exchange: Timing of Uridine Triacetate

The challenge of deciding when to administer uridine triacetate was explored by the panel.

Dr. Schwartzberg: I assume uridine triacetate would work more effectively if given very early; otherwise we would see the same kind of downstream toxicity we see with methotrexate.

Dr. Campen: Exactly, but...

Collaborative Exchange: The Expanded Access Program and Uridine Triacetate

The panel discussed the various aspects of obtaining a drug such as uridine triacetate through the expanded access program.

Ms. Vogel: The expanded access program allows companies to provide patients access to their medicines while the drugs are still in preapproval process, but it is strictly...

Case Studies: Collaborative Practice in Action

The panel presented two case studies—one on high-dose methotrexate toxicity and one on 5-FU toxicity—as a platform for discussion of considerations, challenges, and interconnected roles of oncologists, nurse practitioners, physician assistants, and clinical pharmacists in safely managing patients...