TAP Vol 5 Issue 7 Supplement

Supplement • Volume 5, Issue 7 • May 1, 2014

Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment Proceedings From a Roundtable Discussion, January 26, 2014, St. Petersburg, Florida

Lee S. Schwartzberg, MD, FACP

Wendy H. Vogel, MSN, FNP, AOCNP®

Christopher J. Campen, PharmD, BCPS, BCOP

Medical Director, The West Clinic, Memphis, Tennessee

Oncology Nurse Practitioner, Wellmont Cancer Institute, Kingsport, Tennessee

Clinical Oncology Pharmacist, University of Arizona Cancer Center, Tucson, Arizona

EARN CE CREDIT: Continuing education credit is provided through the Meniscus Educational Institute, a triple accredited provider for CME/CE/CEU credits and contact hours, upon successful completion of the supplement and evaluation.

Editor-in-Chief, James O. Armitage, MD

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities Provided by the Meniscus Educational Institute and The ASCO Post

Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment Proceedings from a roundtable discussion, January 26, 2014, St. Petersburg, Florida 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 educational grant from BTG International, Inc. Meniscus Educational Institute 18 Elizabeth Street, Suite 300 West Conshohocken, PA 19428-2935 Phone: 610-834-1810 Fax: 610-834-8856 E-mail: email@meniscus.com www.meniscus.com © 2014, Meniscus Educational Institute. All rights reserved.

The ASCO Post Published by Harborside Press, LLC 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631-692-0800 Fax: 631-692-0805 E-mail: cara@harborsidepress.com www.harborsidepress.com

Faculty Christopher J. Campen, PharmD, BCPS, BCOP, University of Arizona Cancer Center Lee S. Schwartzberg, MD, FACP, The West Clinic Wendy H. Vogel, MSN, FNP, AOCNP®, Wellmont Cancer Institute

Activity Rationale and Purpose It has been clearly demonstrated that a high-quality and efficient cancer care system requires effective multidisciplinary teams that collaborate to provide patient-centered care. There is a genuine need to provide these practitioners with the skills and training to enable them to confidently carry out their responsibilities successfully.

This activity’s roundtable discussion contained a series of case studies. The participants discussed the cases from the perspective of each of their roles in collaborative practice. The roundtable discussion was used as a basis for the supplement herein. The supplement discussion focuses on the prevention and management of methotrexate- and fluorouracil-­related toxicities, especially with regard to proper dosing, monitoring, and prompt intervention. In addition, the material covers expanded access programs, including their purpose, benefits, and potential concerns.

Intended Audience The program’s target audience consists of physicians, physician assistants, nurse practitioners, nurses, pharmacists, and other allied health professionals specializing in the field of oncology.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities Learning Objectives Upon completion of this activity, participants should be able to: ■■ Discuss the effects of methotrexate- and fluorouracil-induced toxicities on managing cancer ■■ Describe the appropriate strategies for managing methotrexate- and fluorouracil-induced toxicities with the advent of new agents and approaches ■■ Provide strategies to promote collaborative practice initiatives for managing methotrexate- and fluorouracil-induced toxicities ■■ Understand the use of expanded access program

Continuing Education Statement of Credit—Participants who successfully complete this activity (including scoring of a minimum of 70% on the learning assessment, complete and submit the evaluation form with an e-mail address) will be able to download a statement of credit via e-mail.

Physicians. The Meniscus Educational Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Meniscus Educational Institute designates this enduring material activity (271.004-1405-MJ) for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses. This activity (271.004-1405-NJ) for 1.25 contact hours is provided by the Meniscus Educational Institute. The Meniscus Educational Institute is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Accreditation refers to recognition of educational activities only and does not imply approval or endorsement by the Meniscus Educational Institute or the American Nurses Credentialing Center’s Commission on Accreditation of any product mentioned.

Provider approved by the California Board of Registered Nursing, Provider No. 13164, for 1.25 contact hours.

ANCC Accreditation Feedback Line: 1-866-262-9730 The Accreditation Program of the American Nurses Credentialing Center is interested in the opinions and perspectives of the participants in accredited continuing education activities, particularly perspectives related to the presence of perceived bias in an activity Pharmacists. The knowledge-based accredited supplement is intended for pharmacists involved in the care of cancer patients. This educational activity is sponsored by the Meniscus Educational Institute. The Meniscus Educational Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The ACPE Universal Activity Number assigned to this program, for 1.25 contact hours, is 0429-9999-14-005-P. Important Notice Concerning Pharmacy Credits: As of January 1, 2013, a central electronic repository for CPE information will be implemented nationally to enable state boards of pharmacy to efficiently verify CE completion. During registration for any ACPE-accredited program, you will be required to provide a valid NABP e-profile ID (e-PID) number, along with your date of birth (as “MM/DD”), in order to receive credit. No CPE credit will be issued or honored by paper certificate for programs attended after January 1st; however, you may receive, at the discretion of your CPE provider, a courtesy receipt of credit for informational purposes only. Licensed pharmacists and pharmacy technicians can obtain an e-PID number by registering with the CPE Monitor through the NABP website at www.nabp.net.

Financial Disclosures All individuals in positions to control the content of this program (e.g., planners, faculty, content reviewers) are expected to disclose all financial relationships with commercial interests that may have a direct bearing on the subject matter of this continuing education activity. Meniscus Educational Institute has identified and resolved all conflicts of interst in accordance with the Meniscus Educational Institute policies and procedures. Participants have the responsibility to assess the impact (if any) of the disclosed information on the educational value of the activity.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities Faculty Christopher J. Campen, PharmD, BCPS, BCOP, has nothing to disclose.

Lee S. Schwartzberg, MD, FACP, has nothing to disclose.

Wendy H. Vogel, MSN, FNP, AOCNP®, has nothing to disclose.

Education Committe and Planners Jeannine Coronna has nothing to disclose.

Joseph Cupola has nothing to disclose.

Terry Logan, CCMEP, has nothing to disclose.

Molly Thompson has nothing to disclose.

Susan Reckling has nothing to disclose.

Christopher J. Campen, PharmD, BCPS, BCOP, has nothing to disclose.

Lee S. Schwartzberg, MD, FACP, has nothing to disclose.

Wendy H. Vogel, MSN, FNP, AOCNP®, has nothing to disclose.

Content Reviewer Cara Glynn has nothing to disclose.

Glenn Bingle, MD, has nothing to disclose.

Karen Abbas, MS, RN, AOCN, has nothing to disclose.

William A. Bonnell, RPh, has nothing to disclose.

Pilot Study Reviewers Glenn Bingle, MD, has nothing to disclose.

Karen Abbas, MS, RN, AOCN, has nothing to disclose.

William A. Bonnell, RPh, has nothing to disclose.

Disclaimer This activity has been designed to provide continuing education that is focused on specific objectives. In selecting educational activities, clinicians should pay special attention to the relevance of those objectives and the application to their particular needs. The intent of all Meniscus Educational Institute educational opportunities is to provide learning that will improve patient care. Clinicians are encouraged to reflect on this activity and its applicability to their own patient population.

The opinions expressed in this activity are those of the faculty and reviewers and do not represent an endorsement by Meniscus Educational Institute of any specific therapeutics or approaches to diagnosis or patient management.

Product Disclosure This educational activity may contain discussion of published as well as investigational uses of agents that are not approved by the U.S. Food and Drug Administration. For additional information about approved uses, including approved indications, contraindications, and warnings, please refer to the prescribing information for each product.

There is no fee for participating in this activity.

Meniscus Educational Institute 18 Elizabeth Street West Conshohocken, PA 19428 Voice Mail:610-834-1810 Internet: info@meniscusedu.com The Meniscus Educational Institute has a full complement of CE offerings on our Web site, www.meniscus.com.

How to Earn Credit To access the learning assessment and evaluation form online, visit www.meniscusce.com Statement of Credit—Participants who successfully complete this activity (including scoring of a minimum of 70% on the learning assessment and complete and submit the evaluation form with an e-mail address) will be able to download a statement of credit.

The ASCO Post • Volume 5, Issue 7 • Supplement

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

Meet the Panel

B

ased on a roundtable discussion conducted at the first annual JADPRO Live 2014 educational symposium in St. Petersburg, Florida, this supplement centers on strategies for preventing and treating severe side effects associated with methotrexate and fluorouracil (5-FU) from the unique perspectives and shared goals of key members of the health-care team: a clinical pharmacist, a medical oncologist, and a nurse practitioner. Representing these team members on the roundtable panel were:

Christopher J. Campen, PharmD, BCPS, BCOP: Dr. Campen is a Clinical Oncology Pharmacist and Information Technology (IT) Analyst at the University of Arizona Cancer Center, Tucson. Chris is currently on the editorial board of JADPRO; Lee S. Schwartzberg, MD, FACP: Dr. Schwartzberg is Professor of Medicine at the University of Tennessee Health Science Center and Medical Director of The West Clinic in Memphis, Tennessee. Lee has been in private practice in hematology and medical oncology since 1987 and has served as the Medical Director of The West Clinic since 2000; and Wendy H. Vogel, MSN, FNP, AOCNP® (moderator): Oncology Nurse Practitioner, Wellmont Cancer Institute, Kingsport, Tennessee. Wendy is also on the editorial board of JADPRO and serves as co-chair for JADPRO Live.

Faculty discussed the clinical challenges associated with the use of methotrexate and 5-FU, emphasizing the need for education, preparation, continual monitoring, and synchronization through a collaborative exchange to improve outcomes and safety for patients on these two agents.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment Proceedings From a Roundtable Discussion, January 26, 2014, St. Petersburg, Florida

I

t 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.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities 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 Christopher J. Campen, methotrexate ≤ 250 mg/m2, PharmD, BCPS, BCOP 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 Collaborative Exchange: Indications and Dosing The panel discussed the indications and dosing of both 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 patients and their tolerance of the drug.

Ms. Vogel: I think sometimes we get complacent when dealing with commonly used drugs like 5-FU and methotrexate. Here, we are talking about high-

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dose methotrexate: the greater the drug dose, the higher the potential for toxicity.

Dr. Schwartzberg: We also should not ignore the possibility of toxicity issues at lower doses. We use [methotrexate] occasionally as a single agent in the palliative setting and as part of combination therapy for breast cancer. Intermediate-dose methotrexate is used in a narrow group of adult cancers. As for 5-FU, we don’t typically think of it in terms of a low dose or a high dose. 5-FU is interesting because its toxicity is based on the way it is delivered and not so much on the dose that is delivered.

Dr. Campen: 5-FU is very much regimendependent, especially when it is given in its most common fashion, via continuous infusion. There are many different ways of giving it and many different infusion schedules.

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

Assessing patient hydration is imperative for the safety of high-dose methotrexate — Christopher J. Campen, PharmD, BCPS, BCOP

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.

Prevention and Treatment of Methotrexate and Fluorouracil Toxicities Thus, they emphasized the importance of a thorough that an oral prodrug of 5-FU (capecitabine) often has evaluation for third-space fluids to prevent such toxicity. replaced those long 5-FU infusions, given similar pharIt is important for clinicians to be knowledgeable macokinetics and an easier delivery system. of the pharmacokinetics of methotrexate, as they vary Considerations in using leucovorin in conjuncconsiderably among patients due to an assortment of tion with both methotrexate and 5-FU were briefly factors. Among these factors, impaired renal function mentioned during the roundtable discussion. In reand concurrent medications may have the greatest imgard to methotrexate, leucovorin has a clear rescue pact. The analysis of some methotrexate parameters rerole (Table 2). Along with hyperhydration and urine lated to measuring patients’ response to the drug, such alkalization, pharmacokinetically guided leucovorin as creatinine clearance, the plasma concentration-time rescue is a key component in the safe administration curve (AUC), dose, dose intensity, and rate of infusion, of high-dose methotrexate in patients with normal may enable clinicians to identify subgroups of patients renal function.15 However, in regard to 5-FU, this is not the case. Leucovorin actually potentiates the who may have an increased risk of severe toxicity or may activity of 5-FU, because both are part of the same likely experience poor outcomes.9 In addition, sufficient methotrexate elimination may be adversely affected in metabolic pathway within cells. (Leucovorin rescue patients receiving concurrent nonsteroidal antiinflamis discussed further in the section on Strategies for matory drugs (NSAIDs), benzimidazoles, and sulfonPrevention and Monitoring; page 9, and in Table 2, amides (numerous potential methotrexate-drug interpage 8.) actions have been identified, see Table 1).

As for 5-FU, the question of high dose also was debatTypes of Adverse Effects and Toxicities ed, as was the delivery system. 5-FU is one of a few drugs The panel discussed adverse effects that occur with for which the qualitative spectrum of toxicity changes high-dose methotrexate and 5-FU. According to Dr. dramatically with the route of administration.10 For inSchwartzberg, renal toxicity is one of the biggest constance, diverse patterns of toxic effects are seen when bocerns with high-dose methotrexate. The reported inci10 lus schedules are compared with infusional schedules. dence of acute kidney injury with high-dose methotrexFurthermore, many patients treated with a 5-FU–based ate is 1.8% of patients.15 The rate may be higher among patients with diabetes or those who have poor renal regimen have plasma 5-FU levels that are not in the apfunction prior to treatment, added Dr. Campen. propriate therapeutic range,11 so about 50% of patients 12 are underdosed and 10% to 20% are overdosed.

Both the dose and the route of administration of Approximately 85% of 5-FU is converted to inactive methotrexate and 5-FU play a major role in the occurmetabolites by dihydropyrimidine dehydrogenase, and rence of serious complications in some patients. For exonly 1% to 3% of the original 5-FU dose exerts cytotoxic ample, methotrexate can be given in higher doses over effects on tumor cells and normal tissues through anaprolonged intravenous infusions, which require supportbolic actions.13 Dihydropyrimidine dehydrogenase, an ive care measures to prevent unacceptable toxicity.15,16 As for 5-FU, exposure is influenced by the method of 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 TABLE 1: Drugs That Inhibit Renal Excretion of Methotrexate be administered at higher doses over 2 to 5 days and at lower doses conCategory Drug tinuously for weeks. A 48-hour infuIbuprofen, aspirin, naproxen sion of 5-FU is often used in treating NSAIDs patients with colon cancer, said Dr. PCN Penicillin Schwartzberg, but 3- to 5-day infuProton pump inhibitors Omeprazole, lansoprazole, rabeprazole sions of 5-FU are typically still used Amphotericin for upper gastrointestinal malignan- Antifungal cies such as esophageal or gastric Antiviral Acyclovir cancer. Furthermore, continuousCarboplatin, cisplatin, oxaliplatin infusion 5-FU is occasionally used Prior platinum-based chemotherapy as a radiosensitizer in cases of rectal For more information, visit www.drugs.com/drug-interactions/methrotrexate/html cancer. Dr. Schwartzberg explained NSAIDs = nonsteroidal antiinflammatory drugs; PCN = penicillin The ASCO Post • Volume 5, Issue 7 • Supplement

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

TABLE 2: Safety Guidelines for the Continuation and Timing of Leucovorin Rescue

a

•

Leucovorin should not be administered within 2 hours before or after glucarpidase dose because leucovorin is a substrate for glucarpidase.a

•

For the first 48 hours after glucarpidase, administer the same leucovorin dose as given prior to glucarpidase.

•

Beyond 48 hours after glucarpidase, administer leucovorin based on the measured methotrexate concentration.

•

Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold.

•

Therapy with leucovorin should be continued until the patient’s methotrexate plasma concentration has been maintained below the leucovorin treatment threshold for a mininum of 3 days.

•

Continue hydration and alkalinization of the urine as indicated.

Voraxaze (glucarpidase) prescribing information. March 2013.

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

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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

Fig 1: Methotrexate crystal formation in renal tubules.

1

Prevention and Treatment of Methotrexate and Fluorouracil Toxicities 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 Lee Schwartzberg, MD, FACP 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

I would be uncomfortable with any practice that does not empower oncology nurses or nurse practitioners to make immediate decisions when they believe there is a life-threatening situation.

— Lee Schwartzberg, MD, FACP

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 The ASCO Post • Volume 5, Issue 7 • Supplement

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities “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

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TABLE 3: Prevention of Nephrotoxicity From High-Dose Methotrexate

Aggressive hydration Urine alkalization to keep urine pH between 7.0 and 8.5 Leucovorin rescue Close monitoring: • Urine output • Fluid balance (avoid negative balance) • Methotrexate levels • Serum creatinine levels Adapted from Ahmed YA, Hasan Y: Prevention and management of high-dose methotrexate toxicity. J Canc Sci Ther 5:106-112, 2013.

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 healthcare 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 Collaborative Exchange: Indications and Dosing The panel focused on some of the challenges of preventing malfunction of 5-FU pumps.

Dr. Campen: As a pharmacist, I’m always concerned about pump issues. We require double checks of every pump that goes out for 5-FU and pharmacy calculations. We monitor pharmacy technicians to assure accurate doses of 5-FU are placed into IV bags, check to prevent overfill, and look at prefilled IV tubing for any air. Nurses are also trained in the process and provide patient education about what to do if something goes wrong with the pump.

Luckily, we have not had an overdose or pump malfunction that caused an early end to therapy.

Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

Dr. Schwartzberg: I have had pump malfunctions; you cannot be in the business very long without having them. The most common thing that happens is obstruction of the line, so it is more a case of not delivering rather than delivering too much. [Physicians] too instruct patients about their pumps, and when to take out the batteries and call immediately. What are your thoughts on dealing with the residual drug?

Dr. Campen: It is an area of controversy that we too have dealt with in the past at our institution. If a patient comes in early on a 1-day pump, it is much different from a 5-day or 7-day pump. Less than 5% would be a normal amount of bolus delivery, but is there any benefit in doing that? That is the unknown factor. Are you shorting the patient if you stop the infusion early? And sometimes it comes down to toxicity. If the patient has already had a lot of toxicity, giving the remaining drug as a bolus afterward is not in his or her best interest.

Dr. Schwartzberg: [Treatment] definitely needs to be individualized. I am more concerned with the higher dose pumps, when you are doing 1 g/m2 over 4 or 5 days, as opposed to the lower dose in the FOLFOX regimen. Clearly, either one of them can cause problems.

Ms. Vogel: From the nursing side, there is a lot of training involved with educating patients on what to do if something goes wrong with the pump.

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 healthcare 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 Oncolo-

gy 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 Wendy Vogel, MSN, FNP, beholder,” said Dr. Schwartz- AOCNP® berg, 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.

Nurses must be absolutely alert to the CNS changes in their patients receiving methotrexate.

— Wendy Vogel, MSN, FNP, AOCNP®

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 The ASCO Post • Volume 5, Issue 7 • Supplement

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Plasma MTX concentration (µmol/L)

coma, non-Hodgkin lymphoma, or acute lymphoblastic leukemia were given intravenous ≥ 97% reduction within 15 minutes glucarpidase. The result was a 99% or greater sustained reduction in serum methotrexate 100 levels within the first through the last measurements (15 minutes to 40 hours).

10 The question of when to administer glucarpidase has been addressed in the literature, as 1 well as by the panel. Widemann and colleagues found that early intervention with the combination of glucarpidase and leucovorin was highly 0.1 effective in patients with high-dose metho15 min (n=138) trexate-induced renal dysfunction.36 However, 0.01 they noted that severe toxicity and mortality BL 1h 2h 1d 2d 3d 4d 5d 6d 7d 8d (n=156) (n=148) (n=127) (n=102) (n=69) (n=53) (n=40) (n=36) (n=30) (n=25) (n=26) occurred when glucarpidase was administered > 96 hours after the start of methotrexate infuTime after first glucarpidase dose sion.36 According to Dr. Campen, even after 48 hours of elevated serum levels of methotrexate, Fig 2: Glucarpidase reduces plasma methotrexate concentrations, but excellent glucarpidase may be a better option than dialysupportive care is also necessary to reduce morbidity. BL = baseline. Source: Widesis or higher doses of leucovorin. mann BC, et al: Pharmacotherapy 2013 doi: 10.1002/phar.1360.

No major adverse effects have been reportnephrotoxicity. For these patients, the carboxypeptidase ed with glucarpidase.33 In nearly 300 study patients, the enzyme glucarpidase is an effective therapy approach.34 most common side effects were paresthesia, flushing, and Glucarpidase, a recombinant bacterial enzyme, hynausea/vomiting (all 2%).22,35 “Glucarpidase appears to have little toxicity,” noted Dr. Schwartzberg. “Given the drolyzes the carboxyl-terminal glutamate residue from profound and life-threatening effects of methotrexate folic acid and classic antifolates, such as methotrexate.35 Glucarpidase converts methotrexate to its inactive meoverdose, I would have a low threshold to use it, even tabolites, 4-deoxy-4-amino-N10-methylpteroic acid and if a patient was on the borderline of a toxic dose.” Dr. glutamate, and provides an alternate non-renal pathway Campen agreed: “If you have already maximized the for methotrexate elimination in patients with renal dysdose of leucovorin and have not seen patient benefit, you function during high-dose methotrexate treatment. need to think of glucarpidase right away.”

Glucarpidase has been available since 1993 through In fact, the National Comprehensive Cancer Network 33 the FDA’s compassionate-use criteria. The drug was (NCCN) Guidelines for both CNS lymphomas and formally approved by the FDA in January 2012 for the non-Hodgkin lymphoma now include glucarpidase.31,35 For patients with CNS lymphomas who have delayed treatment of toxic plasma methotrexate concentrations methotrexate excretion and high plasma methotrexate (> 1 μmol/L) in patients with delayed methotrexate 35 concentrations, the NCCN guideline notes that early inclearance due to impaired renal function. Patients may be candidates for glucarpidase treatment if they tervention with glucarpidase has demonstrated efficacy have extremely high methotrexate levels, often accomin rapidly reducing these high methotrexate plasma conpanied by renal dysfunction. “You are trying to prevent centrations and preventing severe toxicity39 and should be considered over hemodialysis. Under the supportive the rare side effects such as neurotoxicity and seizures,” care section of the NCCN Non-Hodgkin Lymphoma noted Dr. Campen. Other potential candidates for gluGuidelines,38 the NCCN panel recommends considercarpidase may include those with markedly increased ing the use of glucarpidase if a patient has significant serum creatinine levels, CNS changes (such as probrenal dysfunction and methotrexate levels > 10 μmol lems with speech, vision, or mental function), and exbeyond 42 to 48 hours. treme weakness/fatigue.35 Clinical studies have shown glucarpidase rapidly Nurses must be knowledgeable in glucarpidase adreduces plasma methotrexate concentrations (Figure ministration along with leucovorin and precautions 2).36,37 In a recent study by Widemann and colleagues,37 with its use (Table 4). According to Dr. Campen, 476 patients who developed renal toxicity and delayed glucarpidase is typically given in a single intravenous methotrexate elimination from treatment for osteosarinjection (50 U/kg)35 and begins working almost im-

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities mediately. 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 highdose 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 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 they do compete when given together.

Dr. Schwartzberg: If you continue to give leucovorin, could you abrogate the benefit, because it is a direct competitor for the enzyme?

Dr. Campen: We administer the leucovorin doses well before the glucarpidase and then continue every 6 hours afterward. It does drop the plasma levels of methotrexate significantly in most patients, but it is necessary to continue leucovorin to combat intracellular methotrexate levels.

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

TABLE 4: Nursing Considerations for

Patients Receiving Glucarpidase

General • Select appropriate patient population • Become familiar with its mechanism of action • Know its dosing and scheduling requirements • Promptly identify potential side effects Specific • Monitor patients for allergic reactions • Adjust administration schedule for leucovorin • Monitor methotrexate levels • Monitor renal function laboratory results and urine output • Provide standard-of-care treatment, including leucovorin therapy, hydration, and alkalization of urine

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 highdose 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 The ASCO Post • Volume 5, Issue 7 • Supplement

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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 in emergency 5-FU overdose settings43–45 and is available in the United States under the expanded access program.

Q. Who might benefit from use of uridine triacetate?

A. Patients who have experienced early-onset toxicity from high doses of 5-FU (within 2 to 3 days of infusion) or impaired elimination may be candidates for immediate treatment with uridine triacetate. Patients with known or suspected overexposure to 5-FU as a result of dihydropyrimidine dehydrogenase deficiency also may be candidates for treatment with uridine triacetate.

Q. When should uridine triacetate be given?

A. It seems that the earlier uridine triacetate is given after 5-FU overexposure the better. However, it appears to be of benefit in patients who experience early-onset toxicities (e.g., severe mucositis, fever, diarrhea, and rash) 2 or 3 days after their 5-FU infusion.

Q. What is the expanded access program?

A. The 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 for which there is no comparable or satisfactory alternative therapy outside a clinical trial. In such cases, the potential benefit justifies the potential risks of treatment.

Q. How is uridine triacetate obtained through the expanded access program?

A. A patient’s physician and the drug manufacturer make special arrangements to obtain the drug for the patient. In an emergency situation, the physician can request the drug via telephone or other rapid means of communication, and authorization to ship and use the drug may be given by the U.S. Food and Drug Administration official over the telephone. In addition, the physician 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. Signed informed consent by the patient is also necessary.

Q. How long does it take to get uridine triacetate once requested?

A. In emergency situations, the drug is delivered rapidly, generally the day requested or within the next 24 hours.

Q. Are there cost considerations involved with obtaining and using uridine triacetate?

A. Costs may include the manufacturer’s cost of preparing the drug and the institution’s cost of administering the drug. The cost associated with the use of uridine triacetate may be reimbursed by some health insurers but not all. As for physicians, the cost to provide access to this drug may not be fully compensated, there may be liability issues, and participation requires commitment (contacting the drug manufacturer and filing paperwork).

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

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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.

Prevention and Treatment of Methotrexate and Fluorouracil Toxicities 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 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 this is difficult, because traditionally 5-FU has a very short half-life, about 5 to 10 minutes. The challenge is to know what the levels will be after infusion and to draw 5-FU levels and get a rapid turnaround time on those levels. In many cases, plasma 5-FU levels generally are < 0 μg/L more than 3 hours after cessation of 5-FU dosing.

Dr. Schwartzberg: Are plasma 5-FU levels reliable in this setting? I would think that the drug works intracellularly, so they would not guide you very well.

Dr. Campen: If you start a continuous infusion by pump and look at plasma 5-FU levels, you do get a very reliable measurement of your AUC. But, at the same time, once you stop the pump, you also lose that very quickly too.

Ms. Vogel: So you should give uridine triacetate within the first 24 hours. If you have missed that 24hour window, is it too late?

Dr. Campen: That is the unknown. The goal is to administer uridine triacetate within the first 24 hours, but it can be given up to 96 hours after 5-FU overdose per protocol.

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 lifethreatening toxicity from capecitabine.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities 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, un-

TABLE 5: Sample Protocol for Prevention of Methotrexate Toxicity in Patients Treated for Osteosarcoma

16

Drug interaction check

Pharmacist should review all medications for potential drug interactions with methotrexate.

Assess for pleural effusions or ascites

Consider methotrexate dose decrease of 25% to 50%.

Assess renal function

Creatinine clearance must be > 50 mL/min. If delayed methotrexate clearance occurred with previous cycles, consider a dose decrease of 25% to 50%.

Mucositis

If grade 3 or greater mucositis occurred with previous courses, consider dose of 25% to 50%.

Assess hydration status

Order intravenous fluids at a rate to exceed 200 mL/h to prevent renal dysfunction associated with methotrexate.

Sodium bicarbonate, sodium acetate, or acetazolamide

Check urine pH every void and prior to the start of methotrexate. Urine pH must be > 7. Continue to check every shift until methotrexate level < 0.05 μmol/L. Contact provider if urine pH is < 7.

Methotrexate level 1–24 hours

24-hour goal < 5 μmol/L

Methotrexate level 2–48 hours

48-hour goal < 0.5 μmol/L

Methotrexate level 3–72 hours

72-hour goal < 0.05 μmol/L

Leucovorin 25 mg PO q6h

Start 24 hours after initiation of methotrexate. If concentration at any time point exceeds goal, increase leucovorin dose to 50 mg IV q6h and contact provider for further direction.

Glucarpidase management if necessary

If plasma methotrexate level > 50 μmol/L at 24 hours, > 5 μmol/L at 48 hours, or greater than two standard deviations above the mean methotrexate elimination curve at least 12 hours following methotrexate administration, and serum creatinine increased greater than twofold above baseline (pretreatment with methotrexate) level, consider emergent use of glucarpidase.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

Learning More About Expanded Access Programs

T

he FDA and ASCO have collaborated to create an educational webinar to explain expanded access programs and to clarify the process to access investigational drugs outside a clinical trial. Although it is primarily intended for physicians, the webinar provides valuable information to anyone interested in learning more about expanded access programs.

The program consists of three interactive modules, all with links to key references and resources relevant to the slide content: 1. Introduction to Expanded Access Programs: Presents an explanation of all expanded access programs available 2. Expanded Access Process: Provides information about the process from the perspective of the physician, the FDA, the industry, and the institutional review board 3. Investigator-Sponsor Responsibilities: Furnishes key information regarding the legal responsibilities of physicians as investigators-sponsors For more information, visit http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ AccesstoInvestigationalDrugs/ucm217583.htm. der 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 The ASCO Post • Volume 5, Issue 7 • Supplement

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities 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

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 regulated. Do you see uridine triacetate being a viable option for patients through this program?

Dr. Campen: Yes. This is the perfect example of a drug being available through an expanded access program.

Dr. Schwartzberg: There are some regulatory hoops to jump through, and I would presume that the patient would provide signed informed consent.

Patients should be made to understand the risks and potential benefits of taking the drug.

Dr. Campen: That would also entail costs, including the manufacturer’s cost of preparing the drug, the institution’s costs of administering the drug, and any expenses surrounding that. So cost is a factor to consider. Some types of insurance, not all, will pay for the cost associated with treatment with uridine triacetate.

Ms. Vogel: I would imagine quick delivery of the drug would be vital in many cases.

Dr. Campen: Exactly. Rapid delivery is key.

Ms. Vogel: Can you elaborate on your institution’s protocol to obtain a drug via the expanded access program?

Dr. Schwartzberg: We are familiar with it; and to obtain the drug, we work closely with our research nurses, who participate in this process because they are used to the program’s regulations.

Dr. Campen: We have protocols set in place in our institution, especially because most of the time, we need quick access to the drug (that day or within the next 24 hours).

How to Earn Credit To access the learning assessment and evaluation form online, visit www.meniscusce.com.

Statement of Credit—Participants who successfully complete this activity (including scoring of a minimum of 70% on the learning assessment and complete and submit the evaluation form with an e-mail address) will be able to download a statement of credit.

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Prevention and Treatment of Methotrexate and Fluorouracil Toxicities

Case Studies: Collaborative Practice in Action

T

he 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 through these potentially life-threatening scenarios.

Case 1: High-Dose Methotrexate for a Primary Central Nervous System Lymphoma

A 44-year-old woman has been diagnosed with a primary CNS lymphoma. She is started on a course of high-dose methotrexate (4 g/m2). Within 24 hours, she reports nausea and vomiting. Her serum creatinine level has climbed from 0.7 mg/dL at baseline to 4.6 mg/ dL. She is also found to be hyperkalemic (serum potassium is 5.5 mEq/L).

Given the suspicion of hyperacute renal dysfunction, the panel considered that stopping the infusion immediately would be the first step in the action plan.

“Essentially, her kidneys are not working at all,” said Dr. Schwartzberg. He also suggested that a consultation with a nephrologist would be worthwhile.

In addition, it would be necessary to avoid any other drugs or procedures associated with nephrotoxicity, including a computed tomography (CT) with contrast.

“Contrast dye is forgotten way too often when you get a consultation,” agreed Dr. Campen.” The panel also noted that this patient might be a candidate for dialysis, depending on her fluid balance as well as the rate of the rise of creatinine levels, serum potassium levels, and other electrolyte abnormalities.

Both Drs. Campen and Schwartzberg hailed the role of oncology nurses and nurse practitioners in managing a life-threatening situation such as this one.

“I would be uncomfortable with any practice that does not empower oncology nurses or nurse practitioners to make immediate decisions when they believe there is a life-threatening situation,” said Dr. Schwartzberg.

Even for drugs other than high-dose methotrexate, such as high-dose interleukin 2, which can cause similar severe toxicities, “Nurses need to have a very quick trigger finger on stopping an infusion if that is the case,” Dr. Campen added.

Standard management protocols are essential to guide health-care professionals—some of whom may be unfamiliar with such rare toxic events—to make

the safest medical decisions. Furthermore, along with monitoring renal function, methotrexate levels should be checked again at 24 hours, according to Dr. Schwartzberg.

The general consensus of the panel was that this patient would be an ideal candidate for treatment with glucarpidase. With her elevated methotrexate levels and her nearly hyperacute renal dysfunction, glucarpidase would be a wise choice given outside the range of leucovorin rescue to avoid antagonist activity.

Case 2: 5-FU for Rectal Carcinoma

A 57-year-old man has been diagnosed with rectal carcinoma. He is started on neoadjuvant chemotherapy, which includes continuous 5-FU IV infusion (1,000 mg/m2 per day on days 1‒5) during the first and fifth weeks of therapy. Although the patient is generally in good health (no history of cardiac disease), he has some severe symptoms when he returns on day 5 of his initial 5-FU therapy. He reports a sore mouth (oral mucositis), difficulty breathing, skin rash (erythematous), diarrhea, and extreme fatigue. The patient is admitted to the hospital for hydration and supportive care. Routine laboratory tests reveal significant neutropenia without fever (absolute neutrophil count [ANC] 400 cells/µL), hemoglobin 11.1 g/dL, BUN 56 mg/dL, and serum creatinine 2.4 mg/dL. The panel agreed that the first steps in this case would be to stop the 5-FU, hospitalize the patient, and institute immediate supportive care measures.

“For this patient, uridine triacetate should be considered,” Dr. Campen suggested.

From a nursing standpoint, Ms. Vogel addressed mouth care for a patient with myelosuppression. “He is at risk for infection, so it is extremely important to make sure that we look in his mouth every day,” she said.

As for managing diarrhea, the choice of therapeutic agent may depend on the patient, noted Dr. Campen.

Higher doses of loperamide may be considered, with diphenoxylate/atropine as a possible alternative option.

From there, if diarrhea remains severe, Dr. Campen suggested intravenous fluids. For inpatients, a short course of octreotide is often helpful, Dr. Campen added.51 Two other topics the panel discussed in regard to this case study were the controversial role of genetic testing for dihydropyrimidine dehydrogenase deficiency and the issue of retreatment with lower doses of

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5-FU. According to the panel, dihydropyrimidine dehydrogenase testing may be indicated for this patient with 5-FU toxicity. Such testing is not routinely performed in Dr. Schwartzberg’s community setting or in Dr. Campen’s institution. However, given the clinical evidence showing that genetic variations in the DPYD gene are a major contributing factor to the risk of 5-FU toxicity,18 some advocate routine dihydropyrimidine dehydrogenase testing. “Typically, we wait and test if we get a severe reaction, which is not optimal,” said Dr. Schwartzberg. To add to the dilemma surrounding routine genetic testing, Dr. Campen noted that a patient may have a dihydropyrimidine dehydrogenase deficiency that does not result in severe toxicity.

Ms. Vogel raised the question of retreating a patient with a lower dose of 5-FU. According to the manufacturer, despite lowering the dose of 5-FU on rechallenge in a few patients, toxicity recurred and progressed with higher morbidity.52 Dr. Schwartzberg admitted that the decision to rechallenge a patient with 5-FU after a severe toxic reaction is a difficult one, and other possible treatment options should be considered. If the

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

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patient had a dihydropyrimidine dehydrogenase deficiency, he would not resume 5-FU therapy. “Although 5-FU clearly adds to neoadjuvant radiotherapy, the risk/benefit ratio must be considered. There are other options,” Dr. Schwartzberg added.

Finally, the panel members agreed that uridine triacetate is indicated in this case study. They shared a few thoughts on how best to explain such a situation to the patient. First, the health-care team should inform the patient that such a severe reaction to 5-FU occurs in very few people, and it needs to be treated in the hospital for a few days. An enzyme deficiency may have caused these symptoms, and genetic testing will show whether that is the case. The patient may develop a fever and require antibiotics, and intravenous nutrition may be needed given the severe mucositis.

The patient should be told that upon receiving the antidote (uridine triacetate), symptoms should improve.

However, Dr. Schwartzberg emphasized the importance of setting realistic expectations for the patient and explaining that it is possible that symptoms may get worse before they get better.

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 develop-

Prevention and Treatment of Methotrexate and Fluorouracil Toxicities ment 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

Conclusion Two important aspects regarding contemporary cancer care were demonstrated at this roundtable discussion, held at the JADPRO Live 2014 educational sympo-

Preventing and Managing Toxicities Related to Methotrexate and Fluorouracil ■■ Despite the common use of methotrexate and

fluorouracil (5-FU), many patients receiving these drugs may develop severe and potentially lifethreatening side effects.

■■ These serious adverse drug effects require proper

prevention, early recognition of the signs and symptoms of drug toxicity, and prompt treatment through the collaborative efforts of oncologists, nurse practitioners, and clinical pharmacists to ensure optimal outcomes with minimal morbidity.

■■ Protocols should be in place for all staff to use with

high-dose methotrexate to help prevent and manage toxicities.

■■ Calculation double checks with 5-FU continuous pumps should be performed 100% of the time.

■■ High-dose methotrexate toxicity can be effectively

treated with glucarpidase, an enzyme that rapidly and thoroughly reduces toxic methotrexate plasma levels.

■■ An antidote to acute severe 5-FU toxicity exists

through expanded access availability of uridine triacetate, and successful intervention requires prompt attention by the care delivery team to obtain and administer the drug.

sium. 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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Notes

How to Earn Credit To access the learning assessment and evaluation form online, visit www.meniscusce.com.

Statement of Credit—Participants who successfully complete this activity (including scoring of a minimum of 70% on the learning assessment and complete and submit the evaluation form with an e-mail address) will be able to download a statement of credit.

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The ASCO Post • Volume 5, Issue 7 • Supplement

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