APHON Pediatric Chemotherapy-Biotherapy Renewal

Association of Pediatric Hematology/Oncology Nurses

PEDIATRIC CHEMOTHERAPY AND BIOTHERAPY PROVIDER RENEWAL

Updated Information Packet 2021–2023

Pediatric Chemotherapy and Biotherapy Provider Renewal Updated Information Packet 2021–2023

Acknowledgments .................................................................................................................... 3

Chemotherapy and Biotherapy Administration Standards for Practice and Education…...... 5

Drug Shortages ......................................................................................................................... 6 Mary E. Newman, MSN RN NE-BC CPON © Nemours Center for Cancer and Blood Disorders, Nemours Alfred l. duPont Hospital for Children, Wilmington, DE Fertility Preservation ................................................................................................................ 15 AnnMarie Martinez, MSN RN CPN CPHON® Children’s Hospital at Montefiore, Bronx, NY Neurotoxicities of Chemotherapy and Biotherapy..................................................................22 Maritza Salazar-Abshire, MEd MSN RN CPON® The University of Texas MD Anderson Cancer Center, Houston, TX Small Molecule Inhibitors.........................................................................................................39 Shelly Tolley, BSN RN CPHON®

Primary Children’s Hospital, Salt Lake City, UT Ruth Anne Herring, MSN APRN CPNP CPHON® Pauline Allen Gill Center for Cancer and Blood Disorders, UT Southwestern Medical Center, Dallas, TX

Acknowledgments Since October 2004, the Association of Pediatric Hematology/Oncology Nurses (APHON) has trained more than 30,000 nurses as chemotherapy and biotherapy providers using The Pediatric Chemotherapy and Biotherapy Curriculum . In addition, APHON has trained more than 600 nurses as instructors to teach the material. The most recent edition of the curriculum (the fourth edition) contains updates on chemotherapy and biotherapy agents, safe handling of chemotherapy and biotherapy, and special considerations pertinent to chemotherapy and biotherapy administration. We are grateful to our colleagues who have dedicated their time and expertise to this project. We commend the nurses who have achieved and maintained the Pediatric Chemotherapy and Biotherapy Provider status in order to provide the best care for the children, adolescents, and families they serve. A special thanks is owed to our contributing authors and reviewers:

Kristin M. Belderson, DNP RN-BC CPON® Children’s Hospital Colorado Aurora, CO Robyn A. Blacken, BSN RN CPHON® Boston Children’s Hospital Boston, MA Joan O’Hanlon Curry, MS RN CPNP CPON® MD Anderson Children’s Cancer Hospital Houston, TX Gina Dovi, RN Hackensack University Medical Center Hackensack, NJ

Michelle Gillard, MSN RN CPHON® Phoenix Children’s Hospital Phoenix, AZ Ruth Anne Herring, MSN APRN CPNP CPHON® Pauline Allen Gill Center for Cancer and Blood Disorders, UT Southwestern Medical Center Dallas, TX Colleen Nixon, MSN RN CPHON® Boston Children’s Hospital and Dana-Farber Cancer Institute Boston, MA

Mary Lynn Rae, MSN RN CPHON® Ann and Robert H. Lurie Children’s Hospital of Chicago Chicago, IL Maria Emiluth Ferreras Ramos, BSN RN CPHON® BMTCN® Morgan Stanley Children’s Hospital of New York Presbyterian New York, NY

Anne Marie Sterk, MSN RN CPON® Montefiore Health System Bronx, NY Kerri Yarnell, MA BSN RN CPHON® Memorial Sloan Kettering Cancer Center New York, NY

Chemotherapy and Biotherapy Administration Standards for Practice and Education Safe and consistent administration of chemotherapy and biotherapy to children and adolescents requires specific knowledge and specialized skills. ! Chemotherapy and biotherapy administered to children and adolescents should be provided by registered nurses who have completed APHON’s Pediatric Chemotherapy and Biotherapy Provider Program. ! The Pediatric Chemotherapy and Biotherapy Curriculum, Fourth Edition, offers the specific knowledge required through a didactic course and an online renewal examination. ! A clinical practicum by the employer of the nurse is recommended to validate the clinical skills used in the administration of chemotherapy and biotherapy. A Pediatric Chemotherapy and Biotherapy Provider is a registered nurse who has successfully completed APHON’s Pediatric Chemotherapy and Biotherapy Provider Course and maintained provider status. ! Pediatric Chemotherapy and Biotherapy Provider status is maintained by renewal every 3 years. ! Renewal is obtained by successfully completing an online exam. ! Annual education specific to administration of chemotherapy and biotherapy and skills validation by employers are recommended. The Pediatric Chemotherapy and Biotherapy Curriculum, Fourth Edition Some of the questions in the posttest refer to general chemotherapy/biotherapy information that can be found in The Pediatric Chemotherapy and Biotherapy Curriculum, Fourth Edition. If you do not have the fourth edition available, you may use previous editions as a resource. However, please note that previous editions will not have the most up-to-date information.

Drug Shortages Mary E. Newman, MSN RN NE-BC CPON ©

Learner Outcomes Upon completion of this Pediatric Chemotherapy and Biotherapy Provider Program learning activity 1. the learner will be able to identify the root causes of drug shortages in the United States 2. the learner will be able to describe the impact of drug shortages in pediatric oncology and the ethical considerations related to them 3. the learner will be able to list available resources with the most up-to-date information on current drug shortages in the United States 4. the learner will be able to summarize the positions and recommendations of the Association of Pediatric Hematology/Oncology Nurses on drug shortages in pediatric hematology and oncology.

*****

The APHON Position Paper on Drug Shortages (Bunnell et al., 2020) opens with this statement: The Association of Pediatric Hematology/Oncology Nurses (APHON) affirms that all children have a right to the highest standard of physical and mental health and the right to treatment that maximizes their survival and well-being. Shortages of essential drugs compromise the health and well-being of all children, especially those diagnosed with cancer and blood disorders, who are among the most vulnerable members of society and require added protection. Background Shortages of medications and other essential healthcare resources have a long-standing history. One of the first drugs to be involved in a large-scale shortage was insulin in the 1920s, followed by penicillin in the 1940s. Both drug shortages were attributed to the manufacturers’ inability to produce an adequate supply. At that time, decisions about prioritizing allocations were arbitrary; they were influenced by politics and emotions and were made without public comment. Since 2001, the number of drug shortages in the United States has risen, and over the past decade, shortages of drugs, including chemotherapy drugs and those used in supportive care treatments, have become more common and are lasting longer. The American Society of Health- System Pharmacists (2021) has reported between 174 and 282 active drug shortages each quarter since 2015.

The causes of drug shortages are multifactorial. The U.S. Food and Drug Administration (2019) reports that economic forces are the root cause of drug shortages in the United States. These economic factors include the falling prices of the drugs, declining revenues from sales and the minimal contribution of certain drugs to the company’s overall revenue. A manufacturer has little incentive to invest considerable time and money to produce a drug that will not bring sufficient income to the company to justify that investment. Another contributing factor is the limited availability of raw materials. In 2018, 88% of pharmaceutical ingredients came from non- U.S. sources. Obtaining pharmaceutical ingredients from sources overseas may be cost effective for pharmaceutical manufacturers, but it may also hinder the manufacturer’s timely response to an increase in demand. Additional causes include quality-control problems in manufacturing that create production delays; a limited number of manufacturing companies; and manufacturers’ business decisions, restricted distribution methods, inventory practices, and to a lesser degree, regulatory issues. Impact Drug shortages have a high impact on health, and in pediatric oncology, they have a particularly serious impact. As Bunnell and colleagues (2020, p. 2) note, “Childhood cancer treatment relies on the use of sterile injectable generic agents, which make up the majority of scarce medications and which manufacturers have limited economic incentives to produce.” Pediatric hematologist/oncologist Yoram Unguru reinforced this point in a 2020 APHON webinar, A Dearth of Lifesaving Medications: Scarcity and Shortage in Childhood Cancer : “Costly chemotherapy agents with limited efficacy are rarely, if ever, in short supply, while inexpensive, older, curative drugs are.” Clinical trials have led to a dramatic improvement in childhood cancer survival over the past 5 decades, but drug shortages may negatively affect enrollment in those trials. Furthermore, many of the scarcest drugs have served as the backbone of childhood cancer clinical trials that have led to proven, lifesaving regimens. No adequate substitutes or alternative drugs are available to treat these pediatric patients during a shortage. In 2019, a critical shortage of the drug vincristine had a significant impact on the childhood cancer population because of its widespread use in the treatment of many different childhood cancers. In the case of acute lymphoblastic leukemia (the most common childhood cancer, which accounts for nearly one-quarter of all children with cancer), a shortage of a critically important drug like vincristine means that the current 90% 5-year event-free survival rate for 3,000 U.S. children affected each year may be compromised. Manufacturing of medical devices has also had an impact on drug shortages. For example, Puerto Rico is responsible for $40 billion of the pharmaceuticals market, more than any other state or territory. More than 100 companies that produce pharmaceuticals or medical devices have manufacturing sites in Puerto Rico. Puerto Rico was devastated by Hurricane Maria in 2017. However, the shortage of sterile normal saline that occurred during that time was not actually a

shortage of normal saline; it was rather a shortage of the sterile minibags that were manufactured in Puerto Rico (Unguru, 2020). Those in the field of pediatric oncology have received little guidance for dealing with drug shortages. Figure 1 graphs the percentage of Children’s Oncology Group (COG) principal investigators and pharmacists who indicated that a shortage of chemotherapy agents had affected clinical trials in the period 2013–2015 (Salazar et al., 2015).

Figure 1. Impact of Drug Shortages on Clinical Trials From “The Impact of Chemotherapy Shortages on COG and Local Clinical Trials: A Report from the Children’s Oncology Group,” by E. G. Salazar, M. B. Bernhardt, Y. Li, R. Aplenc, and P. C. Adamson, 2015, Pediatric Blood and Cancer , 62 (6), p. 942 (https://doi.org/10.1002/pbc.25445). Copyright 2015 by Wiley Periodicals, Inc.

Ethical Considerations Children with cancer are particularly vulnerable to the impact of drug shortages, so the shortages present significant ethical challenges (Decamp et al., 2014). Substitute regimens need to be carefully examined before they are adopted because they can result in inferior patient outcomes. APHON does not support unethical practices (such as drug hoarding or discrimination based on patients’ age, developmental level, race, ethnicity, disability, immigration status, or ability to pay) that violate the principle of justice. Unsafe strategies of waste reduction, such as those that violate infection prevention protocols (e.g., reusing drugs, administering expired drugs) or compromise the quality of care are also unethical (Bunnell et al., 2020). It is essential that decision making on drug allocation be founded on ethical principles. Moreover, the healthcare team must ensure that communication with patients and families about drug shortages is explicit and transparent. Ethical issues that may arise in the event of drug shortages may be related to decisions in these areas: delays in treatment, the skipping of a

dose or administration of a lower dose, which patients should receive a scarce drug, what constitutes an adequate reserve, and who makes these decisions. According to Decamp and colleagues (2014), the imperative to prevent and to manage drug shortages is based on two fundamental values: (1) the need to maximize the benefits of highly effective drugs and (2) the obligation to ensure equitable access across patients and patient groups. Decamp et al. (2014, p. e718) made the following recommendations grounded on ethical rationales, and those recommendations were published in a consensus statement in the Journal of the American Academy of Pediatrics : 1. Optimize and efficiently use supplies to reduce the likelihood of future shortages and mitigate their effects. 2. Develop explicit policies that give equal priority during a drug shortage to evidence-based use of chemotherapy agents whether patients are receiving treatment within or outside a clinical trial. 3. Create an improved, centralized clearinghouse for sharing information about drug availability and shortages. 4. Explore voluntary sharing of drugs at state, regional, and national levels. 5. Develop a strategy for ongoing stakeholder engagement regarding managing drug shortages, with specific emphasis on patients and patient advocacy groups. Positions and Recommendations APHON supports the following efforts, as stated in its 2020 position paper on drug shortages (Bunnell et al., 2020, pp. 2–3): ! promoting awareness of drug shortages through reliable information sharing ! a dvocating for strategies that minimize the impact of drug shortages on the quality of care ! cooperating and collaborating with healthcare institutions, consortiums, professional organizations, policy makers, and stakeholders in prioritizing the prevention and management of drug shortages ! advocating for federal, local, and institutional policy changes that address drug shortages and reduce their frequency and impact on patients and families ! d eveloping institutional policies that – describe the institution’s approach to the management of drug shortages – include ethical principles of decision making on drug allocation

– ensure explicit and transparent communication with patients and families about drug shortages ! using evidence-based strategies to minimize the impact of drug shortages by maximizing efficiency and eliminating waste through interventions such as – grouping patients receiving the same therapy into cohorts to share vials during drug preparation – reducing advance preparation of drugs that may lead to waste – using safe dose-rounding practices to eliminate waste – evaluating drugs’ expiration times and shelf life to extend the period of safe drug use ! developing institutional interdisciplinary drug allocation committees that – include physicians, pharmacists, nurses, social workers, members of institutional ethics committees, and patient representatives – apply ethical decision-making principles – explore reasonable therapeutic drug alternatives – make prioritization decisions that are applied equitably to patients affected by drug shortages – provide an appeal process for patients and families who have been affected by drug allocation decisions ! showing respect for patients and caregivers by informing them about drug shortages and the process by which allocation decisions are made.

APHON’s position paper (Bunnell et al., 2020, p. 3) continues by offering these recommendations: that nurses

! become informed both about the causes and impact of drug shortages and about current recommendations to prevent or reduce the impact of drug shortages on public health ! advocate for and participate in institutional drug shortage and allocation committees ! ensure that families receive current and reliable information about drug shortages and the subsequent management plan for their child’s care ! refrain from implementing individual strategies (e.g., drug hoarding) that, although well- intentioned, may compromise the delivery of safe, ethical, and high-quality care

! acknowledge the distress that clinicians experience when forced to implement drug allocation decisions that negatively affect individual patients and families ! provide support and therapeutic communication to patients and families whose treatment is altered because of an insufficient drug supply ! become involved in public policy advocacy that strives to minimize drug shortages. Resources on Current Drug Shortages More information is available from the American Society of Health-System Pharmacists (www.ashp.org) and the U.S. Food and Drug Administration (https://www.fda.gov/drugs/drug- safety-and-availability/drug-shortages). Mitigation and Allocation Strategies A 2017 survey that used the membership list of the American Society of Pediatric Hematology/Oncology (ASPHO) was conducted to assess what personnel were involved in scarce drug prioritization and distribution and what criteria were used to inform decisions about the distribution of scarce drugs (Beck et al., 2017). The survey results revealed a significant disparity between respondents’ judgments about how decisions were currently being made and their views on who should be making them ( Table 1 ).

Table 1. Survey of 191 ASPHO Physicians About Their Experiences of Drug Shortages

How have drug shortages affected patient care?

Physicians who were not able to prescribe a needed medication because of a shortage Physicians who knew of drug shortages at their institutions but had not yet been directly affected

65%

79%

Who provided you with information about drug shortages?

Pharmacist Another physician A website Nurses

98% 41% 38% 7%

Does your institution have a drug shortage policy?

Yes No Unsure

62% 4% 33%

At your institution, who makes decisions on the allocation of drugs during a shortage?

Pharmacist Physician Hospital administration Panel Ethics committee Do not know

70% 60% 23% 18% 4% 25%

Who should make decisions on the allocation of drugs during a shortage?

Pharmacist Physician Hospital administration Panel Ethics committee Nurse Parent Not sure

80% 83% 19% 42% 19%

4% 3% 7%

Adapted from “Physician Approaches to Drug Shortages: Results of a National Survey of Pediatric Hematologist/Oncologists,” by J. C. Beck, B. Chen, and B. G. Gordon, 2017, World Journal of Clinical Oncology , 8 (4), 336–342; table 2, p. 338 (https://doi.org/10.5306/wjco.v8.i4.336). Copyright 2017 by the authors. Licensed under CC-BY-NC 4.0, https://creativecommons.org/licenses/by-nc/4.0/legalcode.

Summary Drug shortages prevent clinicians from providing a reasonable standard of care. Drugs that are critical in pediatric oncology and that have contributed to a dramatic improvement in childhood cancer survival over the past 5 decades are among the scarcest drugs. It is essential that those making decisions on drug allocation be guided by established ethical principles and that institutions establish interdisciplinary drug allocation committees. Pediatric hematology/oncology nurses play a key role in advocating for and participating in such committees as well as ensuring that families receive current and reliable information about drug shortages and the subsequent plans for managing their child’s care. References American Society of Health-System Pharmacists. (2021). Drug Shortages Statistics. www.ashp.org/Drug-Shortages/Shortage-Resources/Drug-Shortages-Statistics Beck, J. C., Chen, B., & Gordon, B. G. (2017). Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists. World Journal of Clinical Oncology , 8 (4), 336–342. https://doi.org/10.5306/wjco.v8.i4.336 Bunnell, D., Burke, S., Casey, M., Hartley, J., & Hubrig, C. (2020). APHON position paper on drug shortages . Association of Pediatric Hematology/Oncology Nurses. https://resources.aphon.org/view/455238775/2/ Decamp, M., Joffe, S., Fernandez, C. V., Faden, R. R., Unguru, Y., & Working Group on Chemotherapy Drug Shortages in Pediatric Oncology. (2014). Chemotherapy drug shortages

in pediatric oncology: A consensus statement. Pediatrics , 133 (3), e716–e724. https://doi.org/10.1542/peds.2013-2946 Salazar, E. G., Bernhardt, M. B., Li, Y., Aplenc, R., & Adamson, P. C. (2015). The impact of chemotherapy shortages on COG and local clinical trials: A report from the Children's Oncology Group. Pediatric Blood and Cancer, 62 (6), 940–944. https://doi.org/10.1002/pbc.25445 Unguru, Y. (2020). A dearth of lifesaving medications: Scarcity and shortage in childhood cancer [Webinar]. Association of Pediatric Hematology/Oncology Nurses. Self-paced course available for purchase at https://apps.aphon.org/store/product-details?productId=17270302 U.S. Food and Drug Administration. (2019). Drug shortages: Root causes and potential solutions . https://www.fda.gov/media/131130/download

Fertility Preservation AnnMarie Martinez, MSN RN CPN CPHON ®

Learner Outcomes Upon completion of this Pediatric Chemotherapy and Biotherapy Provider Program learning activity 1. the learner will be able to distinguish methods of fertility preservation according to pubertal status 2. the learner will be able to list six high-risk gonadotoxic chemotherapies. ***** Advances in the treatment of childhood cancers have been on the rise, resulting in a remarkable 5-year overall survival rate of 85.1% for children diagnosed with cancer from 0 to 19 years of age, based on Surveillance, Epidemiology, and End Results (SEER) data from November 2020 (Howlader et al., 2021). Although this statistic is very promising, cancer treatments can result in subfertility, infertility, or sterility. Fertility preservation for pediatric patients should be discussed as soon as possible after the cancer diagnosis, regardless of the patient’s reproductive age. This section will cover normal reproductive physiology; the indications for fertility preservation; methods of fertility preservation, which are determined by the patient’s pubertal status; and counseling needs, barriers, and ethical and cultural considerations related to fertility preservation. Normal Reproductive Physiology The differences in male and female reproductive physiology determine the methods of fertility preservation available, and the options available for prepubertal boys and girls are minimal. In boys, spermatogenesis, though it occurs before puberty, does not lead to the production of mature sperm, or spermatozoa. Spermarche , or release of the spermatozoa, occurs in early to mid-puberty (ages 13 to 18 years). In girls, oogenesis occurs during fetal development. Mature oocyte development begins with menarche and occurs with each ovulation cycle (Klipstein et al., 2020). Indications for Fertility Preservation It is estimated that one in three people will get cancer at some point. Because survival rates are improving, the number of survivors whose reproductive future is in question is significant. For most cancers, the treatment involves a combination of two or more modalities, including chemotherapy, radiotherapy, surgical intervention, and immunotherapy. With the exception of immunotherapy, for which effects on fertility are now yet known, all these modalities can cause permanent infertility. The effects of chemotherapy and radiotherapy on the gonads are dose

dependent; Table 1 presents the risks associated with various doses of radiation given in various locations.

Table 1. Risk of Infertility Associated with Radiation Therapy Doses and Sites

High Risk

Intermediate Risk

Total body irradiation for bone marrow transplant or stem cell transplant

Testicular radiation dose 1–6 Gy from scattered pelvic or abdominal radiation Pelvic or whole-abdominal radiation dose 5–10 Gy in postpubertal girls

Testicular radiation dose >2.5 Gy in adult men

Testicular radiation dose ≥6 Gy in prepubertal boys Pelvic or whole-abdominal radiation dose 10–15 Gy in prepubertal girls

Pelvic or whole-abdominal radiation dose ≥6 Gy in adult women Pelvic or whole-abdominal radiation dose ≥10 Gy in postpubertal girls Pelvic or whole-abdominal radiation dose ≥15 Gy in prepubertal girls

Craniospinal radiotherapy dose ≥25 Gy

Adapted from “Fertility Preservation for Young Adults, Adolescents, and Children with Cancer,” by K. A. Rodriguez-Wallberg, A. Anastacio, E. Vonheim, S. Deen, J. Malmros, and B. Borgström, 2020, Upsala Journal of Medical Sciences, 125 (2), 112–120; table 1, p. 114. https://doi.org/10.1080/03009734.2020.1737601. Copyright 2020 by the authors. Licensed under CC- BY-NC 4.0, https://creativecommons.org/licenses/by-nc/4.0/legalcode.

Although the connection between the radiotherapy dose and risks to fertility is clear, the connection is less clear for chemotherapy drugs. With chemotherapy, it is difficult to quantify the specific effects of individual drugs when they are given as part of a treatment regimen over time. Table 2 presents what we currently know about gonadotoxicity related to chemotherapy drugs for both males and females (Rodriguez-Wallberg et al., 2020). With females, gonadotoxicity is age-dependent because females are born with a finite quantity of oocytes that declines over time until menopause is reached, whereas spermatogenesis continues throughout a male’s lifespan. Pediatric diagnoses that have the highest risk of permanent sterility are testicular cancer, leukemia, and Ewing sarcoma (Del-Pozo-Lérida et al., 2019).

Table 2. Risk of Infertility Related to Chemotherapy Agents

High Risk

Intermediate Risk Low Risk

Unknown Risk

Busulfan Chlorambucil Cyclophosphamide Ifosfamide Melphalan Nitrogen mustard Procarbazine

Carboplatin with low cumulative dose Cisplatin with low cumulative dose Doxorubicin

Treatment protocols for Hodgkin lymphoma without alkylating agents Actinomycin D Bleomycin 5-Fluorouracil Methotrexate Radioiodine treatment for thyroid cancer Vincristine

Bevacizumab Erlotinib Imatinib Irinotecan

Paclitaxel and docetaxel for treatment of breast cancer Trastuzumab

Adapted from “Fertility Preservation Young Adults, Adolescents, and Children with Cancer: Medical and Ethical Considerations,” by K. A. Rodriguez-Wallberg, A. Anastacio, E. Vonheim, S. Deen, J. Malmros, and B. Borgström, 2020, Upsala Journal of Medical Sciences, 125 (2), 112–120; table 2, p. 115. https://doi.org/10.1080/03009734.2020.1737601. Copyright 2020 by the authors. Licensed under CC-BY-NC 4.0, https://creativecommons.org/licenses/by-nc/4.0/legalcode.

Methods for Preservation of Male Fertility Prepubertal

Gonadal and gamete preservation in prepubertal males is challenging because many proposed treatment modalities (with the exceptions of shielding the testes or moving them out of the radiation field) are currently experimental. Most experimental methods include hormone manipulation or preserving a sample of testicular tissue. Studies in animals suggest that cryopreservation of testicular tissue, autotransplantation, xenotransplantation, and in vitro maturation have the potential to be successful; however, these methods still need to be tested in humans. Effective pharmacological interventions have yet to be identified (Klipstein et al., 2020). Postpubertal Once postpubertal males start producing mature sperm, the options for fertility preservation change. The current options are sperm cryopreservation and testicular tissue cryopreservation, with sperm cryopreservation from masturbation being the most effective (Klipstein et al., 2020). The procedure for sperm collection should be performed before the initiation of treatment. Ideally, the collection would consist of at least 3 semen samples with a period of abstinence for 48 hours between each sample. In some cases, collection of the samples must occur within the

same day because of the nature of the diagnosis and in order to prevent a delay in treatment (Del-Pozo-Lérida et al., 2019). Alternative methods of semen collection besides masturbation include testicular aspiration, electroejaculation under sedation, or retrieval from a urine sample post masturbation (Klipstein et al., 2020). Gonadal shielding is an option for those receiving radiotherapy and in which sperm collection is not possible. At the current time, testicular tissue cryopreservation should only be performed as part of a clinical trial or approved experimental protocols (Oktay et al., 2018).

Methods for Preservation of Female Fertility Prepubertal

As with fertility preservation for prepubertal males, fertility preservation for prepubertal females (with the exception of gonadal shielding and oophoropexy) is primarily experimental. For patients who will receive radiation therapy to the pelvis, the ovaries can be transposed (surgically relocated out of the field of radiation therapy). However, oocytes are very sensitive to radiation, and only 15% of patients who choose to undergo transposition of their ovaries will achieve the goal of becoming pregnant. Gonadal shielding is another option for ovarian protection during radiation therapy; however, it is less effective if the patient receives gonadotoxic chemotherapy in addition to radiotherapy (Klipstein et al., 2020). In the United States, an open trial is being held to assess the safety and efficacy of cryopreservation of ovarian tissue in prepubertal females. Thus far we have no evidence that use of the autotransplanted tissue can lead to pregnancy and delivery. In addition, tissue harvested from a patient at diagnosis could potentially be contaminated with leukemia cells, and this tissue could reintroduce leukemia cells into the patient’s body during a future autotransplant. Postpubertal Fertility preservation options for postpubertal females include oocyte or embryo cryopreservation. Although embryo preservation had previously been the only available option, oocyte cryopreservation has shifted from being considered an experimental method to being recommended in 2012 by the American Society of Reproductive Medicine (Klipstein et al., 2020). In embryo cryopreservation, the oocytes are fertilized with the sperm of a partner or an anonymous donor. This practice involves a larger number of social, emotional, and ethical considerations, which require a certain level of maturity. Now that oocyte cryopreservation has been recommended and proven successful, embryo cryopreservation is recommended for use only in rare circumstances. The oocyte cryopreservation is an invasive and lengthy process. It requires 10 days of transvaginal ultrasonography and blood tests, followed by a surgically performed transvaginal oocyte retrieval. Depending on the diagnosis and clinical status of the patient, the delay of a treatment regimen for 10 days or more may not be possible (Klipstein et al., 2020). Of note, even though contradictory evidence exists for the use of gonadotropin- releasing hormone (GnRH) or ovarian suppression, the 2018 American Society of Clinical Oncology (ASCO) guidelines suggest that in situations in which established fertility preservation methods (i.e. cryopreservation of oocytes, embryos, or ovarian tissue) are not possible, “GnRH

may be offered to patients with the hope of reducing chemotherapy-induced ovarian insufficiency” (Oktay et al., 2018). Counseling Needs According to ASCO guidelines, all patients with a cancer diagnosis should be counseled about the impact that their disease and treatment regimen may have on their future fertility (Lee et al., 2006). Such counseling is best done immediately after diagnosis (which is admittedly a very stressful moment in the patient’s life) but before initiation of the treatment regimen. For preadolescent patients, it is recommended that the conversation involve one or both parents. However, for adolescent patients, it may be best to have the conversations without a parent present. Such conversations may be embarrassing, but the goal is to help patients understand their options, allow them to ask questions, gain their assent, and allow them to take an active role in their care. This counseling should start with their provider, who can then make referrals to specialists in fertility preservation: reproductive endocrinologists, surgeons, mental health professionals, urologists, and child life personnel (Klipstein et al., 2020).

Barriers Providers and Timing

The single most critical barrier to fertility preservation is the first consultation. The emotional stress, anxiety, and fear that accompany a new cancer diagnosis often provoke the desire to start the treatment regimen right away. However, beginning treatment before addressing fertility concerns may impair reproduction or limit reproduction options (Klipstein et al., 2020). A review of studies shows that providers do not hold these conversations with patients and families for a number of reasons. The barriers reported include providers’ lack of knowledge about treatment- induced fertility impairments and fertility preservation procedures, the perceived need to begin the patient’s treatment immediately, estimates of the patient’s likelihood of survival, discomfort discussing fertility, and sometimes even assumptions about their patients’ preferences (Lampic & Wettergren, 2019). The consequence of these barriers is a significant information gap for the patients. In one study, only half of the parents surveyed recalled receiving fertility information, and approximately one third expected normal fertility following the cancer treatment (van den Berg & Langeveld, 2008). Another study of adolescents with cancer revealed that 81% would want to proceed with investigational or research-based alternatives in an attempt to maintain their fertility (Burns et al., 2006). Economic Factors Cryopreservation can cost hundreds of dollars a year, and that is added to the cost of the collection process, depending on the option chosen (Klipstein et al., 2020). Fertility preservation is not covered by most insurance plans, so it is often an out-of-pocket expense for patients. This situation is changing in a number of states, where new legislation is mandating insurance coverage for fertility preservation (Halpern et al., 2020).

Ethical and Legal Considerations Pediatric fertility preservation raises several ethical and legal concerns. First and foremost is the obtaining of consent (for older patients) or assent (for younger patients); the specified ages vary by state. Disagreements between the parent and the adolescent child are difficult to manage. The critical concern in this situation is the extent of involvement of the minor child. The patient’s family and the medical team should work together to provide an open future for the patient. The principle of an open future rests on the moral duty to protect the rights of children, especially in relation to important decisions being made before the child reaches the age of consent. For adolescent patients, it is recommended that their feelings about such decisions be solicited without a parent or guardian present. It is also important to have these conversations regardless of a child’s sexual orientation. When conflict occurs, it is prudent to hold a consultation with an ethics professional or a mental health professional. Any disposition of gametes should be delayed until the child reaches the age of consent. For children who do not survive into adulthood, their eggs and ovarian tissue or sperm and testicular tissue should be destroyed. This practice is consistent with recommendations made by the American Society for Reproductive Medicine (Ethics Committee of the American Society for Reproductive Medicine, 2013). References Burns, K. C., Boudreau, C., & Panepinto, J. A. (2006). Attitudes regarding fertility preservation in female adolescent cancer patients. Journal of Pediatric Hematology/Oncology , 28 (6), 350– 354. https://doi.org/10.1097/00043426-200606000-00006 Del-Pozo-Lérida, S., Salvador, C., Martínez-Soler, F., Tortosa, A., Perucho, M., & Giménez-Bonafé, P. (2019). Preservation of fertility in patients with cancer (Review). Oncology Reports , 41 (5), 2607–2614. https://doi.org/10.3892/or.2019.7063 Ethics Committee of the American Society for Reproductive Medicine (2013). Posthumous collection and use of reproductive tissue: A committee opinion. Fertility and Sterility , 99 (7), 1842–1845. https://doi.org/10.1016/j.fertnstert.2013.02.022 Halpern, J. A., Das, A., Faw, C. A., & Brannigan, R. E. (2020). Oncofertility in adult and pediatric populations: Options and barriers. Translational Andrology and Urology , 9 (Suppl 2), S227– S238. https://doi.org/10.21037/tau.2019.09.27 Howlader N., Noone, A. M., Krapcho, M., Miller, D, Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D. R., Chen, H. S., Feuer, E. J., & Cronin, K. A. (Eds). (2021). SEER Cancer Statistics Review (CSR), 1975–2018, National Cancer Institute. https://seer.cancer.gov/csr/1975_2018/, based on November 2020 SEER data submission, posted to the SEER web site, April 2021.

Klipstein, S., Fallat, M. E., Savelli, S., Committee on Bioethics, Section on Hematology/Oncology, & Section on Surgery. (2020). Fertility preservation for pediatric and adolescent patients with cancer: Medical and ethical considerations. Pediatrics , 145 (3), e20193994. https://doi.org/10.1542/peds.2019-3994 Lampic, C., & Wettergren, L. (2019). Oncologists’ and pediatric oncologists’ perspectives and challenges for fertility preservation. Acta Obstetricia et Gynecologica Scandinavica , 98 (5), 598–603. https://doi.org/10.1111/aogs.13551 Lee, S. J., Schover, L. R., Partridge, A. H., Patrizio, P., Hamish Wallace, W., Hagerty, K., Beck, L. N., Brennan, L. V., & Oktay, K. (2006). American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of Clinical Oncology , 24 (18), 2917–2931. https://doi.org/10.1200/JCO.2006.06.5888 Oktay, K., Harvey, B. E., Partridge, A. H., Quinn, G. P., Reinecke, J., Taylor, H. S., Hamish Wallace, W., Wang, E. T., & Loren, A. W. (2018). Fertility preservation in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology , 36 (19), 1994–2001. https://doi.org/10.1200/JCO.2018.78.1914 Rodriguez-Wallberg, K. A., Anastacio, A., Vonheim, E., Deen, S., Malmros, J., & Borgström, B. (2020). Fertility preservation for young adults, adolescents, and children with cancer. Upsala

Journal of Medical Sciences , 125 (2), 112–120. https://doi.org/10.1080/03009734.2020.1737601

van den Berg, H., & Langeveld, N. E. (2008). Parental knowledge of fertility in male childhood cancer survivors. Psycho-Oncology , 17 (3), 287–291. https://doi.org/10.1002/pon.1248

Neurotoxicities of Chemotherapy and Biotherapy Maritza Salazar-Abshire, MEd MSN RN CPON ®

Learner Outcomes Upon completion of this Pediatric Chemotherapy and Biotherapy Provider Program learning activity 1. the learner will be able to describe the two main components of the nervous system 2. the learner will be able to recognize commonly used chemotherapy agents that cause neurotoxicity in the pediatric oncology patient population 3. the learner will be able to identify neurotoxicities caused by immunotherapy and targeted therapy agents used to treat pediatric oncology patients.

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Peripheral and Central Nervous Systems: An Overview The nervous system controls our reflexes, movements, actions, and sensations, continuously controlling who we are and what we do. A complex collection of nerves that are connected to our brain and spinal cord, it is divided into two main parts: the central nervous system and the peripheral nervous system ( Figure 1 ). Together the parts of the nervous system work to transmit signals between the brain and the rest of the body. These signals control our ability to move, breathe, see, and think, among many other daily activities.

Figure 1. Central and Peripheral Nervous Systems The central nervous system consists of the brain and the spinal cord. The peripheral nervous system is made up of nerves that branch off from the spinal cord and extend to all parts of the body. From Lumen Learning, 2021. https://courses.lumenlearning.com/suny-wmopen-biology2/chapter/components-of- the-nervous-system/. Licensed under CC-BY-NC 4.0, https://creativecommons.org/licenses/by/4.0/legalcode. As with any other system or organ in our bodies, both the central and peripheral nervous systems are affected by chemotherapy and immunotherapy toxicities. Toxicities can be acute and may resolve as soon as the therapy is discontinued or completed, while other toxicities are chronic and may become long term effects of the chemotherapy or immunotherapy that was administered. This section will review some of the more common chemotherapies that have neurotoxic effects associated with them. Novel immunotherapies that have neurotoxic side effects will also be discussed.

Neurotoxicities of Chemotherapy Antimetabolites

Cytarabine. Cytarabine is a cell-cycle-specific antimetabolite used for the treatment of hematologic malignancies; it can be administered intravenously, intrathecally, or subcutaneously. When cytabarine is administered in high doses, patients may develop acute cerebellar syndrome. Symptoms include gait disturbance, seizures, and in some cases, death (Sioka & Kyritsis, 2009). Lower doses of cytarabine have also been associated with posterior reversible encephalopathic syndrome (PRES) (Peddi et al., 2014). Patients with PRES, formerly known as reversible posterior leukoencephalopathy, can present with headache, impaired level of consciousness, confusion, visual disturbances, seizure, nausea, vomiting, encephalopathy, and focal neurologic deficits (Gillard et al., 2019; Peddi et al., 2014). Hypertension has also been frequently observed in patients during the days or hours leading up to the PRES event. PRES can

be reversible when the cytarabine or agent contributing to the syndrome is discontinued; however, in some cases symptoms have persisted after discontinuation of the offending drug. Methotrexate. Methotrexate is a mainstay antineoplastic for hematologic malignancies and solid tumors alike. It can be administered through a variety of routes: oral, subcutaneous, intramuscular, intravenous, and intrathecal (IT). Methotrexate neurotoxicity, however, is typically associated with doses that are administered intrathecally or high intravenous doses (Peddi et al., 2014). There are several neurotoxicities associated with intrathecal administration of methotrexate including aseptic meningitis and transverse myelopathy. Aseptic meningitis should be considered in the differential for a patient exhibiting symptoms such as headache, stiff neck, mild fever, nausea and vomiting several hours after an intrathecal dose of methotrexate (Verstappen et al., 2003). Symptoms of aseptic meningitis due to IT methotrexate administration can last anywhere between 12 and 72 hours (Verstappen et al., 2003). Transverse myelopathy may occur after several IT methotrexate injections and can include symptoms of back pain that may radiate to the legs, sensory loss, bowl and bladder dysfunction and paraplegia. Thankfully, this toxicity is not long lasting and will resolve on its own (Peddi et al., 2014). Delayed methotrexate neurotoxicity or encephalopathy can also be found in patients who have received high intravenous doses of methotrexate or those who have received IT doses of methotrexate. This delayed leukoencephalopathy may occur six months or more after methotrexate administration and can be chronic. Symptoms of delayed methotrexate neurotoxicity include: progressive dementia, gait disturbances, hemiparesis, aphasia seizure and death. Radiation therapy administered concurrently with methotrexate has been associated with increased risk for developing delayed leukoencephalopathy (Peddi et al., 2014). A rare but potential complication of intrathecal methotrexate therapy may also include changes in the white matter that can manifest as a transient or persistent neurologic dysfunction. This neurologic dysfunction can first appear as facial nerve weakness, speech disturbance, seizures, hemiparesis, or an obtunded level of consciousness. It usually occurs within 2 weeks of a patient’s receiving intrathecal therapy (Bhojwani et al., 2014). The nurse caring for a patient exhibiting these signs and symptoms after receiving intrathecal methotrexate should advocate for further work-up and imaging to rule out white matter changes (Ramli et al., 2020; Yim et al., 1990). 5-fluorouracil. 5-fluorouracil (5-FU) is a cell-cycle-specific antimetabolite that is given to treat germ cell tumors and hepatoblastoma in the pediatric oncology setting, but it can also be used to treat gastrointestinal, head and neck, and breast cancers. Administration can be intravenous or by mouth. Patients with a deficiency of the dihydropyrimidine dehydrogenase enzyme are at greater risk for 5-FU-related toxicities, including neurotoxicities, because this enzyme is responsible for the metabolic clearance of 5-FU from the body. This drug does cross the blood- brain barrier, and high concentrations of 5-FU can be found in the cerebellum. As a result, cerebellar toxicity can be seen with this drug. Symptoms of cerebellar toxicity include ataxia, dysarthria, dysmetria, extraocular muscle abnormalities, optic nerve neuropathy, and extrapyramidal symptoms. Leukoencephalopathy, although rare, has also been reported with 5- FU administration (Peddi et al., 2014).

Fludarabine. Fludarabine is an antimetabolite given to treat acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and as an agent in hematopoietic stem cell transplant (HSCT) preparative regimens. Neurotoxicity is rare when fludarabine is administered in standard doses. However, severe neurotoxicity syndrome has been described when the drug is administered at doses greater than 40 mg/m 2 /day. Blindness, encephalopathy, and coma are symptoms of the diffuse, necrotizing leukoencephalopathy that is the severe neurotoxicity syndrome associated with high doses of fludarabine (Sioka & Kyritsis, 2009). Nelarabine. Nelarabine, approved for use in treating T-cell ALL and T-cell lymphoma, is a prodrug of a purine antimetabolite, arabinofuranosylguanine (ara-G). It is metabolized in cells to the metabolite ara-G triphosphate (ara-GTP). Cell death results from the incorporation of ara-GTP into DNA. The cytotoxic effects of ara-GTP were found to have a 20 times greater effect on T cells than on B cells, and it was therefore approved by the U.S. Food and Drug Administration (FDA) for use in T-cell hematologic malignancies in 2005. It should be noted that nelarabine’s package insert contains a black-box warning for severe neurotoxicity, including mental status changes, severe somnolence, headache, paresthesia, dysesthesia, dizziness, seizures, and peripheral neuropathy, which can range from numbness and paresthesias to motor weakness and paralysis. These neurotoxicities were noted in both pediatric and adult patients. Nursing considerations include frequent monitoring during treatment and up to 24 hours after treatment, because neurotoxicity can be dose limiting. Adverse reactions related to demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome have been reported. It has also been noted that patients who have undergone intrathecal chemotherapy or are concurrently undergoing intrathecal chemotherapy or craniospinal radiation while receiving nelarabine may have increased severity of neurotoxic effects (Ngo et al., 2015). Neurotoxicity associated with nelarabine may be transient or may be long-lasting. Correlation between neurotoxicity and dose and/or concurrent intrathecal chemotherapy has also been found. Alkylating Agents Cyclophosphamide and ifosfamide . Cyclophosphamide and ifosfamide are both cell-cycle- nonspecific alkylating agents that are used for a variety of solid tumor malignancies. Cyclophosphamide is also used in treating hematologic malignancies and as an agent in preparative regimens for HSCT. Cyclophosphamide has been reported to have minimal neurotoxic effects. Blurred vision, dizziness, and confusion have all been reported but found to be reversible. Ifosfamide has been associated with an acute encephalopathy characterized by somnolence, hallucinations, agitation, and seizures that may lead to coma and even death. This encephalopathy, also referred to as ifosfamide neurotoxicity, can develop hours to days into a course of ifosfamide, and methylene blue can be used to treat the encephalopathy (Sioka & Kyritsis, 2009). Ifosfamide has also been linked to peripheral neuropathies in patients receiving the drug for bone and soft tissue sarcomas. This axonal peripheral neuropathy (arising from the axon of a nerve cell; Figure 2 ) can be quite painful and may discourage patients from ambulating on their own (Frisk et al., 2001).

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