- Email: [email protected]
Development of a Nursing Policy for the Administration of an Oncolytic Virus in the Outpatient Setting
ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2019) 150928
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Development of a Nursing Policy for the Administration of an Oncolytic Virus in the Outpatient Setting Vania Hom, BSN, RN, OCNÒ *, Emoke Karonis, MSN, RN, CRNI, Tara Sigidi, BSN, RN, OCNÒ , Kristin Cawley, MSN, RN, OCNÒ Memorial Sloan Kettering Cancer Institute, New York, NY
A R T I C L E
I N F O
Keywords: Oncolytic virotherapy Immunotherapy Oncolytic viruses Clinical trial Oncologic nursing
A B S T R A C T
Objective: To describe the development of a nursing policy for the administration of oncolytic viruses in therapeutic clinical trials and the unique challenges for infection control and nursing. Data Source: Journal articles, web-based resources, peer-reviewed literature. Conclusion: Early nursing involvement and inclusion of multidisciplinary hospital departments facilitated the creation of a nursing policy that maintained fidelity to the research protocol and minimized potential risk to nursing staff. A total of 18 doses of oncolytic viruses were administered with no inadvertent exposures to staff or other patients of the oncolytic virus. Implications for Nursing Practice: Nursing should be involved at the initiation of a clinical trial to determine whether policies need to be created or changed to maintain the integrity of the research protocol while ensuring the safety of staff and patients. © 2019 Elsevier Inc. All rights reserved.
History of Oncolytic Viruses Using viruses to treat cancer is an emerging treatment modality. This involves using different viruses to target and replicate in tumor cells, thereby stimulating the immune system to recognize and attack the tumor.1 The first reported observation of cancer remission following an incidental viral infection was described over a century ago. Since then, research and engineering of oncolytic viruses (OV) have become more sophisticated through genetic engineering to specifically target cancer cells and activate the host immune response against tumors.1 Early research in the 1950s used first-generation, or wild-type, attenuated viruses such as the West Nile virus and adenovirus to treat lymphoma and cervical cancer, respectively.2 However, these early studies did not include the details required to replicate results, such as how patients were dosed or how tumor response was assessed.2 OVs would be more precise, though, if they only entered tumor cells and normal, healthy cells were not infected and lysed. In the 1990s, second-generation viruses were genetically altered to target tumor cells for entry and replication. More recently, third-generation OV have been engineered with genes for the protein granulocyte-macrophage colony stimulating factor (GM-CSF), which increases host immune responses.2
* Address correspondence to: Vania Hom, BSN, RN, OCNÒ , Memorial Sloan Kettering Cancer Institute, 160 East 53rd St., New York, NY 10022. E-mail address: [email protected] (V. Hom). https://doi.org/10.1016/j.soncn.2019.08.007 0749-2081/© 2019 Elsevier Inc. All rights reserved.
The first third-generation OV was approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of advanced melanoma. Talimogene laherparepvec, known as T-VEC, is a herpes simplex virus (type 1) that is directly injected into melanoma tumors in the skin.3 Two genes were deleted to prevent the virus from entering normal, healthy neurons, and genes for GM-CSF were added.4 While T-VEC directly infects and lyses the tumor cells at the injection site, it also may trigger a systemic immune response that can induce tumor regression at untreated, distant metastatic sites.3,5 However, antitumor response in lesions that were not injected was only 13%, compared with 67% of directly injected tumors. This suggests that TVEC may be best used in conjunction with other anti-cancer therapies, such as chemotherapy or immune checkpoint inhibitors.3 With the FDA approval of T-VEC, the scientific community recognized that OV therapy may become more widely utilized in oncology. Yet, with this promising new treatment option came several unknowns. A New Route of Administration At this National Cancer Institute-designated cancer center, interest in exploring the utility of OV led to the initiation of a phase 1 clinical trial using an OV administered via intraperitoneal (IP) catheter to treat peritoneal carcinomatosis secondary to epithelial ovarian or colorectal cancer. While T-VEC was a modified herpesvirus, the OV used in this research study was ONCOS-102, a genetically engineered adenovirus. T-VEC was directly injected into lesions via needle and syringe,5,6 but IP infusion of an OV did not have a pre-existing
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standard of care. Treatment with chemotherapy through an internalized IP catheter accessed via a port had been the standard of care for ovarian cancer since 2006, and the placement of a external drainage catheter for palliation of ascites is common. However, there were various operational and clinical unknowns associated with administration of an OV through this route. An OV has a different mechanism of action and presents different potential risks than a chemotherapeutic agent. In contrast to chemotherapy, toxicities such as fever, chills, or flu-like symptoms are common adverse events.7 Environmental contamination or shedding of an OV may pose a hazard to immunocompromised or other vulnerable individuals, so a process needed to be developed to clean touchable surfaces and limit the spread of bodily fluids of patients treated with an OV. A concern unique to OV is the potential for the engineered virus to recombine with the wild-type virus, which may result in a more virulent strain.8 Therefore, biosafety questions of patients, staff, and hospital administration needed to be discussed and addressed when developing the standard of care for the safe administration of an OV. Many similar safety questions, such as personal protective equipment (PPE) requirements, drug preparation and transport, and need for an occlusive dressing were addressed by this cancer center when intratumoral injection of T-VEC was introduced.6 However, IP viral drug infusion had not previously been used in the adult oncology population at this medical center. The route of administration of ONCOS-102 through an IP catheter precipitated the need for a new institutional nursing policy. Challenges to Address When implementing change, it is crucial that all stakeholders be involved from the very beginning. The interrelated, interconnected multidisciplinary team can exchange ideas centered on the importance of diversity of the team and any information already available on issues and trends related to the policy. Non-clinical staff offered important insights in streamlining and anticipating operational issues. The implementation of IP OV administration required policy development to be a participatory process by all stakeholders. Involved stakeholders included nursing leadership from Education, Clinical Trials, Phase 1/2 Infusion, and Administration. Nursing was joined by representatives from the physician team, Pharmacy, Infection Control (IC), Interventional Radiology, Environmental Services, and Supply Distribution/Facilities. These stakeholders would ensure all concepts that impact patient care and staff safety were considered. Four primary areas were addressed: patient care delivery, mitigating exposure, communication, and education. Patient care delivery Clinical nursing experts from Chemotherapy, Evidence-Based Practice, Interventional Radiology and Pediatrics, as well as the catheter manufacturer, were consulted regarding experience with the IP catheter and its feasibility as an infusion device. Infusion by means of a catheter developed for drainage required analysis of similar techniques (peritoneal dialysis, IP port, intra-vesicular chemotherapy) and how they could be applied to fit this scenario. A procedure for the accessing, de-accessing, connectivity, and maintenance of the catheter went through several revisions before being finalized. Mitigating exposure Experience with a previous OV, a coxsackie virus, which shared similarities to ONCOS-102 in relation to mode of transmission and rate of infectivity, provided a base on which to begin the development a formal policy regarding exposure with OV. Droplet and contact guidelines from infectious disease for coxsackie and adenovirus were used to determine protective measures, such as how the 21-day window of contagion or shedding once the patient was treated with
the OV was established. In collaboration with IC, the clinical team, Environmental Services, and Informatics, developed a prospective patient care plan for possible entry, circulation, and exit points within the health care system. Figure 1 was the result of this analysis, depicting the anticipated workflow and path of the patient on an OV treatment day. A risk assessment was performed in areas where a patient may need to receive care, such as the laboratory, physician clinics, infusion unit, waiting areas, and emergency entry points. The risk assessment would help to identify possible exposure to other patients receiving care in the building as well as other staff. This also identified intersecting clinical areas with personnel that would require education. From this assessment, the following processes were put into place. To minimize potential exposure, a dedicated infusion room was prepared in advance when a patient was scheduled for an OV treatment. This ensured the patient could be escorted directly into the room upon arrival to minimize possible OV exposure to other vulnerable patients. This room would be prepared the night before the patient’s arrival and the treating nurse would be identified in advance so that he/she could prepare accordingly. Room preparation included a biohazard sign on the door, stocking of PPE supplies immediately outside of the room, and anticipated supplies for the day within the room, as well as biohazard waste bags and bins for the proper disposal of used supplies. All laboratory assessments, physical examinations, treatment, and observation were performed in the same room to minimize patient travel throughout the building. Biological Safety Level (BSL) is a system defined by the US Centers for Disease Control and Prevention that indicates the level of precautions that a microbe or biological agent requires to reduce risk of exposure to staff or environmental contamination.9 Most drugs prepared in the pharmacy are classified as BSL-1 and present minimal hazards to persons.9 Drugs that require BSL-2 containment pose a moderate risk to persons handling them; and the area used for reconstitution requires features such as restricted access, secure and temperature-monitored storage, and personnel trained in handling BSL-2 organisms.9 At this facility, all BSL-2 agents had to be prepared in the pharmacy under a dedicated negative-pressure hood early in the morning before any other drugs were processed. This hood was then out of use for an hour while undergoing the cleaning and ventilation process, thereby potentially causing delays in the preparation of other drugs that day. Because the OV required BSL-2 hazardous containment and had to be prepared very early in the morning, there were logistical challenges that involved the timing of drug preparation, drug stability, and subsequent window of time for drug administration. There was only one treatment room in the infusion unit that met the requirements for OV infusion because a single-patient room with a door was required per protocol directives. Therefore, patients had to be scheduled for early morning appointments, and the infusion unit had to ensure room availability to prevent treatment delays. To avoid possible transport hazards, the preparation and delivery of drug was limited to pharmacists and the treating nurse. The treating nurse was assigned and aware of role at least 1 day prior to ensure an orderly and timely process on the day of treatment. The treating nurse picked up the OV from the pharmacy wearing PPE. Coordination between the pharmacy, infusion unit, and patient scheduling was necessary to ensure that the drug did not expire before it could be infused. Nurses were initially apprehensive regarding their ability to control their exposure to what was perceived as a concentrated source of infection. The educational plan included steps to take with spill exposure from the infusion bag or catheter leakage. Current USP800 guidelines https://www.usp.org/compounding/general-chapter-haz ardous-drugs-handling-healthcare, along with droplet precautions, were consistently reinforced. Droplet precautions were maintained because it was the institutional standard to provide outpatients
ARTICLE IN PRESS V. Hom et al. / Seminars in Oncology Nursing 00 (2019) 150928
Fig. 1. Operational flow for an OV therapy patient.
diagnosed with the adenovirus with a facemask and a separate waiting area. Similar to chemotherapy, spillage of the OV was to be controlled and cleaned based on volume spilled with bleach as the primary virucidal disinfecting agent. As with chemotherapy, paper towels or similarly absorptive material would be used to mop up liquids and disposed in a biohazard waste bag, contaminated area(s) would be wiped with bleach or 70% ethanol alcohol, and PPE would be worn when cleaning spills. Feedback from nursing staff regarding personal concerns such as pregnancy or chronic illness was welcomed and managed privately, based on IF guidelines and staffing considerations. Communication Because patients receiving OV require care from various departments throughout the large organization, it is crucial that clear communication amongst the interdisciplinary teams is established. To
Fig. 2. Example of OV sticker label on a catheter dressing.
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V. Hom et al. / Seminars in Oncology Nursing 00 (2019) 150928
achieve this, multiple techniques were used. One of the first communications was between Interventional Radiology and the Clinical Trials team. Because IP catheters are usually placed for drainage of ascites but these patients did not have ascites, Interventional Radiology needed to be aware that placement in this case was for investigational use. This was done either via e-mail communication or in the order for the IP catheter placement. After placement, a sticker label was placed at the site of the IP catheter (Fig. 2). The sticker was developed to be a visual cue for any person who encounters the patient, even outside the organization, that the catheter was not a typical drainage catheter. The sticker denoted the name of the agent infused through the catheter, ONCOS-102, the infusion date, and droplet as type of IF measure. The date of infusion was usually the date of the last dressing change, so it was important to help track the weekly dressing changes and mark the beginning of the period of IF precautions. Another communication aid was an alert in the patient’s electronic medical record that identified the patient as requiring special isolation precautions. At our institution, the IF indicator was entered as “Special Study Droplet Precautions” in the header of the patient’s electronic medical record. This header was discontinued manually by the clinical trials team 21 days after the last OV infusion. Education Education was necessary for both the members of the health care team as well as patients and caregivers. Patient education materials created for patients receiving OV and caregivers focused on management of the catheter and its dressing, as well as the nature of the OV and potential side effects. Patients were provided supplies for each visit that included masks and gloves. They were also given additional supplies to take home (paper tape, gloves, alcohol wipes, “OV Catheter Sticker Labels,” and catheter dressings). These were used if the integrity of the dressing became compromised, soiled, or loose. They were given written educational materials about the purpose and rationale for OV therapy, as well as emergency contact information. patients receiving OV and their caregivers would have access to the clinical team both during business hours and through an answering service that connected them to the covering physician on nights and weekends. Patients and caregivers were educated on the rationale for droplet precautions. Caregivers were encouraged to not remain in the room during the infusion to minimize exposure risk, and were instructed to wear a gown, gloves, and mask while in the room with the patient, once the infusion had been initiated. After receiving their first infusion, patients were deemed infectious and were educated to wear a mask and gloves upon entering and exiting their treatment room. At each weekly visit the dressing for the IP catheter, clamps and needleless connectors were changed in the chemotherapy unit, or if the dressing became soiled or wet. For clinical staff, a 1-hour didactic education program under the supervision of the Clinical Nurse Specialist was conducted to validate staff competency in OV therapy, as well as administration using an internalized IP port and external IP catheter designed for drainage. This program was offered multiple times to reach all staff. The program included a PowerPoint presentation lasting approximately 30 minutes with a competency check list and return demonstration. The opportunity to explore and familiarize the staff with the catheter was made with an improvised patient model with catheter inserted and dressing applied. Figure 3 is the patient model created for nursing staff to practice connecting the IP catheter to the OV infusion and example catheter dressing and label placement. This provided an opportunity for nurses to ask questions and develop confidence in using the catheter in an unpressured environment. Nurses were later supervised and validated as competent in the administration procedure under the observation of a nursing educator and senior RN already competent.
Fig. 3. Model of a patient abdomen and catheter dressing.
Outcomes At the time of writing, three patients were successfully treated with ONCOS-102 a total of 18 doses of OV with no transmission of virus between staff or patients. There has been no incidence of peritonitis, local infection, or catheter dislodgement. Nurses have been able to administer the OV with confidence and without adverse events related to the administration procedure or inadvertent exposure. Nurses verbalized comfort in caring for patients receiving OV in the ambulatory setting via this mode of administration. Discussion Nurses are instrumental in ensuring the safety of staff and patients. As novel oncology treatments emerge, the role of the nurse in establishing standards becomes even more important, but not without challenges. The implementation of IP OV therapy is a true exemplar of why nursing involvement is critically important at the initiation of a new clinical trial. Without it, safety processes and policies may not be established in a timely fashion or adverse events may occur from the absence of these systems being in place. With new treatments, there is little to no evidence to guide what measures should be implemented. In the absence of this, nurses must utilize expert opinion and similar clinical precedent to determine what constitutes adequate protection of staff, patient, and environment. The measures established in this institution’s policy were based on those used for T-VEC administration,6,10 universal biohazard precautions,11 and internal experts in employee safety and IF measures. Exposure of staff and other patients to viral shedding and subsequent infection was theoretically possible; however, there have been no reported cases of infection in household members of a patient treated with OV.12 However, there have been accidental exposures of health care personnel while handling T-VEC, such as needlestick and eye exposure.10 Aside from requiring treatment with antiviral medication, serious sequelae do not seem to have been reported in these known exposures.10 Nonetheless, vigilance in transporting the OV, handling spills, cleaning of environmental surfaces, and disposal of waste contaminated with OV is essential to reduce risk.12 In the absence of clear
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safety assurances, there can be a degree of uncertainty regarding how conservatively to proceed regarding IF measures, and as such policies were developed with an abundance of caution. It will be necessary to re-evaluate these measures as OV become more prevalent and more research is available. As an example, a decade ago T-VEC had to be administered in a negative-pressure room in the United Kingdom, but now can be safety given in a standard ambulatory setting.10 Another decision that had to be made was regarding the length of time patients treated with ONCOS-102 were required to maintain safety precautions. In the initial phase 1 study of 12 patients, infective viral particles were found in the urine and saliva of one patient and in the saliva only of two patients 3 days after dosing.13 However, ONCOS102 had been administered intravenously in these patients; patients in which ONCOS-102 had been given intratumorally did not have any samples with viral particles.13 Whether viral particles were found at further time points was either not studied or not reported. It was unknown whether viral particles would be found in the body fluids of patients who received IP ONCOS-102, and for how long after treatment. Another question not addressed was whether these viral particles were potentially infective. Although it was difficult to find evidence for how long treated patients should be maintained on safety precautions, a lack of evidence does not equate to a lack of risk to others. It is recommended from this experience to consider the four interrelated topics described when developing a nursing policy for a novel agent and process. What appeared to be a simple need to create a policy for the administration of an OV resulted in a careful look at the health care system and coordination of departments outside of nursing. Office administration and patient scheduling had to be aware of the need for early morning appointments. The medical team had to also be available early in the day, and be aware to see the patient in the infusion room, not in the clinic. Pharmacy had to reserve personnel and hood time for the reconstitution of the viral drug. Institutions who require a similar policy should map the path of both the OV agent and that of the patient to determine where coordination with other departments is required. Questions that should be asked could be: What is that department’s workflow and how would the new policy impact them? What education would be required? How would this education be delivered, or how would staff obtain the information needed to provide optimal patient care? Such questions should be addressed before the first patient is treated. Conclusion The infusion of OV treatment via an IP catheter was an unfamiliar administration approach requiring skillful collaboration involving many stakeholders. In this case, it was led by nursing to ensure patient and staff safety, regulatory alignment, as well as unit
5
readiness. It was imperative that nurses from clinical trials, infusion, and leadership jointly develop this policy to ensure successful implementation. We strongly recommend that nursing be involved at site initiation of a new clinical trial. Nurses at institutions who are considering the use of OV in clinical trials should first determine whether a new nursing policy needs to be developed and whether the administering nurses will require additional education. If so, carefully consider the non-nursing departments that should be aware and involved, such as IF, pharmacy, and environmental services. Staff that will be responsible for administering the OV product should be fully educated on techniques and risks. Patients should be educated as well, per protocol informed consent and recommendations; any dressings and facility-specific requirements for IF should be reinforced by nursing staff. Efforts continue in evaluating safety measures and revision of standards as we receive more knowledge from these clinical trials. Early nursing involvement and inclusion of multidisciplinary hospital departments facilitated the creation of a nursing policy that maintained fidelity to the research protocol and minimized potential risk to nursing staff. References 1. Jhawar SR, Thandoni A, Bommareddy PK, et al. Oncolytic viruses natural and genetically engineered cancer immunotherapies. Front Oncol. 2017;7(202). 2. Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol. 2007;4:101–117. 3. Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene Iaherparepvec: first in class oncolytic virotherapy. Hum Vaccin Immunother. 2018;14:839–846. 4. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. 5. Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66:1249–1264. 6. Wall LM, Baldwin-Medsker A. Safe and effective standards of care. Clin J Oncol Nurs. 2017;21:E260–E266. 7. Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3:841–849. 8. Bujis PRA, Verhagen JHE, van Eijck CHJ, van den Hoogen BG. Oncolytic viruses: from bench to bedside with a focus on safety. Hum Vaccin Immunother. 2015;11:1573–1584. 9. Centers for Disease Control and Prevention. Recognizing the biosafety levels. Available at: https://www.cdc.gov/training/QuickLearns/biosafety/. Accessed 13 June, 2019. 10. Harrington KJ, Michielin O, Malvehy J, et al. A practical guide to the handling and administration of talimogene laherparepvec in Europe. Onco Targets Ther. 2017;10:3867–3880. 11. Broussard IM, Kahwaji CI. Universal precautions [Updated March 16, 2019]. StatPearls. Treasure Island. FL: StatPearls Publishing; 2019. https://www.ncbi.nlm.nih. gov/books/NBK470223/. Accessed 4 June 2019. 12. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–662. 13. Ranki T, Pesonen S, Hemminki A, et al. Phase I study with ONCOS-102 for the treatment of solid tumors an evaluation of clinical response and exploratory analysis of immune markers. J Immunother Cancer. 2016;4:17.
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Development of a Nursing Policy for the Administration of an Oncolytic Virus in the Outpatient Setting Vania Hom, BSN, RN, OCNÒ *, Emoke Karonis, MSN, RN, CRNI, Tara Sigidi, BSN, RN, OCNÒ , Kristin Cawley, MSN, RN, OCNÒ Memorial Sloan Kettering Cancer Institute, New York, NY
A R T I C L E
I N F O
Keywords: Oncolytic virotherapy Immunotherapy Oncolytic viruses Clinical trial Oncologic nursing
A B S T R A C T
Objective: To describe the development of a nursing policy for the administration of oncolytic viruses in therapeutic clinical trials and the unique challenges for infection control and nursing. Data Source: Journal articles, web-based resources, peer-reviewed literature. Conclusion: Early nursing involvement and inclusion of multidisciplinary hospital departments facilitated the creation of a nursing policy that maintained fidelity to the research protocol and minimized potential risk to nursing staff. A total of 18 doses of oncolytic viruses were administered with no inadvertent exposures to staff or other patients of the oncolytic virus. Implications for Nursing Practice: Nursing should be involved at the initiation of a clinical trial to determine whether policies need to be created or changed to maintain the integrity of the research protocol while ensuring the safety of staff and patients. © 2019 Elsevier Inc. All rights reserved.
History of Oncolytic Viruses Using viruses to treat cancer is an emerging treatment modality. This involves using different viruses to target and replicate in tumor cells, thereby stimulating the immune system to recognize and attack the tumor.1 The first reported observation of cancer remission following an incidental viral infection was described over a century ago. Since then, research and engineering of oncolytic viruses (OV) have become more sophisticated through genetic engineering to specifically target cancer cells and activate the host immune response against tumors.1 Early research in the 1950s used first-generation, or wild-type, attenuated viruses such as the West Nile virus and adenovirus to treat lymphoma and cervical cancer, respectively.2 However, these early studies did not include the details required to replicate results, such as how patients were dosed or how tumor response was assessed.2 OVs would be more precise, though, if they only entered tumor cells and normal, healthy cells were not infected and lysed. In the 1990s, second-generation viruses were genetically altered to target tumor cells for entry and replication. More recently, third-generation OV have been engineered with genes for the protein granulocyte-macrophage colony stimulating factor (GM-CSF), which increases host immune responses.2
* Address correspondence to: Vania Hom, BSN, RN, OCNÒ , Memorial Sloan Kettering Cancer Institute, 160 East 53rd St., New York, NY 10022. E-mail address: [email protected] (V. Hom). https://doi.org/10.1016/j.soncn.2019.08.007 0749-2081/© 2019 Elsevier Inc. All rights reserved.
The first third-generation OV was approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of advanced melanoma. Talimogene laherparepvec, known as T-VEC, is a herpes simplex virus (type 1) that is directly injected into melanoma tumors in the skin.3 Two genes were deleted to prevent the virus from entering normal, healthy neurons, and genes for GM-CSF were added.4 While T-VEC directly infects and lyses the tumor cells at the injection site, it also may trigger a systemic immune response that can induce tumor regression at untreated, distant metastatic sites.3,5 However, antitumor response in lesions that were not injected was only 13%, compared with 67% of directly injected tumors. This suggests that TVEC may be best used in conjunction with other anti-cancer therapies, such as chemotherapy or immune checkpoint inhibitors.3 With the FDA approval of T-VEC, the scientific community recognized that OV therapy may become more widely utilized in oncology. Yet, with this promising new treatment option came several unknowns. A New Route of Administration At this National Cancer Institute-designated cancer center, interest in exploring the utility of OV led to the initiation of a phase 1 clinical trial using an OV administered via intraperitoneal (IP) catheter to treat peritoneal carcinomatosis secondary to epithelial ovarian or colorectal cancer. While T-VEC was a modified herpesvirus, the OV used in this research study was ONCOS-102, a genetically engineered adenovirus. T-VEC was directly injected into lesions via needle and syringe,5,6 but IP infusion of an OV did not have a pre-existing
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V. Hom et al. / Seminars in Oncology Nursing 00 (2019) 150928
standard of care. Treatment with chemotherapy through an internalized IP catheter accessed via a port had been the standard of care for ovarian cancer since 2006, and the placement of a external drainage catheter for palliation of ascites is common. However, there were various operational and clinical unknowns associated with administration of an OV through this route. An OV has a different mechanism of action and presents different potential risks than a chemotherapeutic agent. In contrast to chemotherapy, toxicities such as fever, chills, or flu-like symptoms are common adverse events.7 Environmental contamination or shedding of an OV may pose a hazard to immunocompromised or other vulnerable individuals, so a process needed to be developed to clean touchable surfaces and limit the spread of bodily fluids of patients treated with an OV. A concern unique to OV is the potential for the engineered virus to recombine with the wild-type virus, which may result in a more virulent strain.8 Therefore, biosafety questions of patients, staff, and hospital administration needed to be discussed and addressed when developing the standard of care for the safe administration of an OV. Many similar safety questions, such as personal protective equipment (PPE) requirements, drug preparation and transport, and need for an occlusive dressing were addressed by this cancer center when intratumoral injection of T-VEC was introduced.6 However, IP viral drug infusion had not previously been used in the adult oncology population at this medical center. The route of administration of ONCOS-102 through an IP catheter precipitated the need for a new institutional nursing policy. Challenges to Address When implementing change, it is crucial that all stakeholders be involved from the very beginning. The interrelated, interconnected multidisciplinary team can exchange ideas centered on the importance of diversity of the team and any information already available on issues and trends related to the policy. Non-clinical staff offered important insights in streamlining and anticipating operational issues. The implementation of IP OV administration required policy development to be a participatory process by all stakeholders. Involved stakeholders included nursing leadership from Education, Clinical Trials, Phase 1/2 Infusion, and Administration. Nursing was joined by representatives from the physician team, Pharmacy, Infection Control (IC), Interventional Radiology, Environmental Services, and Supply Distribution/Facilities. These stakeholders would ensure all concepts that impact patient care and staff safety were considered. Four primary areas were addressed: patient care delivery, mitigating exposure, communication, and education. Patient care delivery Clinical nursing experts from Chemotherapy, Evidence-Based Practice, Interventional Radiology and Pediatrics, as well as the catheter manufacturer, were consulted regarding experience with the IP catheter and its feasibility as an infusion device. Infusion by means of a catheter developed for drainage required analysis of similar techniques (peritoneal dialysis, IP port, intra-vesicular chemotherapy) and how they could be applied to fit this scenario. A procedure for the accessing, de-accessing, connectivity, and maintenance of the catheter went through several revisions before being finalized. Mitigating exposure Experience with a previous OV, a coxsackie virus, which shared similarities to ONCOS-102 in relation to mode of transmission and rate of infectivity, provided a base on which to begin the development a formal policy regarding exposure with OV. Droplet and contact guidelines from infectious disease for coxsackie and adenovirus were used to determine protective measures, such as how the 21-day window of contagion or shedding once the patient was treated with
the OV was established. In collaboration with IC, the clinical team, Environmental Services, and Informatics, developed a prospective patient care plan for possible entry, circulation, and exit points within the health care system. Figure 1 was the result of this analysis, depicting the anticipated workflow and path of the patient on an OV treatment day. A risk assessment was performed in areas where a patient may need to receive care, such as the laboratory, physician clinics, infusion unit, waiting areas, and emergency entry points. The risk assessment would help to identify possible exposure to other patients receiving care in the building as well as other staff. This also identified intersecting clinical areas with personnel that would require education. From this assessment, the following processes were put into place. To minimize potential exposure, a dedicated infusion room was prepared in advance when a patient was scheduled for an OV treatment. This ensured the patient could be escorted directly into the room upon arrival to minimize possible OV exposure to other vulnerable patients. This room would be prepared the night before the patient’s arrival and the treating nurse would be identified in advance so that he/she could prepare accordingly. Room preparation included a biohazard sign on the door, stocking of PPE supplies immediately outside of the room, and anticipated supplies for the day within the room, as well as biohazard waste bags and bins for the proper disposal of used supplies. All laboratory assessments, physical examinations, treatment, and observation were performed in the same room to minimize patient travel throughout the building. Biological Safety Level (BSL) is a system defined by the US Centers for Disease Control and Prevention that indicates the level of precautions that a microbe or biological agent requires to reduce risk of exposure to staff or environmental contamination.9 Most drugs prepared in the pharmacy are classified as BSL-1 and present minimal hazards to persons.9 Drugs that require BSL-2 containment pose a moderate risk to persons handling them; and the area used for reconstitution requires features such as restricted access, secure and temperature-monitored storage, and personnel trained in handling BSL-2 organisms.9 At this facility, all BSL-2 agents had to be prepared in the pharmacy under a dedicated negative-pressure hood early in the morning before any other drugs were processed. This hood was then out of use for an hour while undergoing the cleaning and ventilation process, thereby potentially causing delays in the preparation of other drugs that day. Because the OV required BSL-2 hazardous containment and had to be prepared very early in the morning, there were logistical challenges that involved the timing of drug preparation, drug stability, and subsequent window of time for drug administration. There was only one treatment room in the infusion unit that met the requirements for OV infusion because a single-patient room with a door was required per protocol directives. Therefore, patients had to be scheduled for early morning appointments, and the infusion unit had to ensure room availability to prevent treatment delays. To avoid possible transport hazards, the preparation and delivery of drug was limited to pharmacists and the treating nurse. The treating nurse was assigned and aware of role at least 1 day prior to ensure an orderly and timely process on the day of treatment. The treating nurse picked up the OV from the pharmacy wearing PPE. Coordination between the pharmacy, infusion unit, and patient scheduling was necessary to ensure that the drug did not expire before it could be infused. Nurses were initially apprehensive regarding their ability to control their exposure to what was perceived as a concentrated source of infection. The educational plan included steps to take with spill exposure from the infusion bag or catheter leakage. Current USP800 guidelines https://www.usp.org/compounding/general-chapter-haz ardous-drugs-handling-healthcare, along with droplet precautions, were consistently reinforced. Droplet precautions were maintained because it was the institutional standard to provide outpatients
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Fig. 1. Operational flow for an OV therapy patient.
diagnosed with the adenovirus with a facemask and a separate waiting area. Similar to chemotherapy, spillage of the OV was to be controlled and cleaned based on volume spilled with bleach as the primary virucidal disinfecting agent. As with chemotherapy, paper towels or similarly absorptive material would be used to mop up liquids and disposed in a biohazard waste bag, contaminated area(s) would be wiped with bleach or 70% ethanol alcohol, and PPE would be worn when cleaning spills. Feedback from nursing staff regarding personal concerns such as pregnancy or chronic illness was welcomed and managed privately, based on IF guidelines and staffing considerations. Communication Because patients receiving OV require care from various departments throughout the large organization, it is crucial that clear communication amongst the interdisciplinary teams is established. To
Fig. 2. Example of OV sticker label on a catheter dressing.
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V. Hom et al. / Seminars in Oncology Nursing 00 (2019) 150928
achieve this, multiple techniques were used. One of the first communications was between Interventional Radiology and the Clinical Trials team. Because IP catheters are usually placed for drainage of ascites but these patients did not have ascites, Interventional Radiology needed to be aware that placement in this case was for investigational use. This was done either via e-mail communication or in the order for the IP catheter placement. After placement, a sticker label was placed at the site of the IP catheter (Fig. 2). The sticker was developed to be a visual cue for any person who encounters the patient, even outside the organization, that the catheter was not a typical drainage catheter. The sticker denoted the name of the agent infused through the catheter, ONCOS-102, the infusion date, and droplet as type of IF measure. The date of infusion was usually the date of the last dressing change, so it was important to help track the weekly dressing changes and mark the beginning of the period of IF precautions. Another communication aid was an alert in the patient’s electronic medical record that identified the patient as requiring special isolation precautions. At our institution, the IF indicator was entered as “Special Study Droplet Precautions” in the header of the patient’s electronic medical record. This header was discontinued manually by the clinical trials team 21 days after the last OV infusion. Education Education was necessary for both the members of the health care team as well as patients and caregivers. Patient education materials created for patients receiving OV and caregivers focused on management of the catheter and its dressing, as well as the nature of the OV and potential side effects. Patients were provided supplies for each visit that included masks and gloves. They were also given additional supplies to take home (paper tape, gloves, alcohol wipes, “OV Catheter Sticker Labels,” and catheter dressings). These were used if the integrity of the dressing became compromised, soiled, or loose. They were given written educational materials about the purpose and rationale for OV therapy, as well as emergency contact information. patients receiving OV and their caregivers would have access to the clinical team both during business hours and through an answering service that connected them to the covering physician on nights and weekends. Patients and caregivers were educated on the rationale for droplet precautions. Caregivers were encouraged to not remain in the room during the infusion to minimize exposure risk, and were instructed to wear a gown, gloves, and mask while in the room with the patient, once the infusion had been initiated. After receiving their first infusion, patients were deemed infectious and were educated to wear a mask and gloves upon entering and exiting their treatment room. At each weekly visit the dressing for the IP catheter, clamps and needleless connectors were changed in the chemotherapy unit, or if the dressing became soiled or wet. For clinical staff, a 1-hour didactic education program under the supervision of the Clinical Nurse Specialist was conducted to validate staff competency in OV therapy, as well as administration using an internalized IP port and external IP catheter designed for drainage. This program was offered multiple times to reach all staff. The program included a PowerPoint presentation lasting approximately 30 minutes with a competency check list and return demonstration. The opportunity to explore and familiarize the staff with the catheter was made with an improvised patient model with catheter inserted and dressing applied. Figure 3 is the patient model created for nursing staff to practice connecting the IP catheter to the OV infusion and example catheter dressing and label placement. This provided an opportunity for nurses to ask questions and develop confidence in using the catheter in an unpressured environment. Nurses were later supervised and validated as competent in the administration procedure under the observation of a nursing educator and senior RN already competent.
Fig. 3. Model of a patient abdomen and catheter dressing.
Outcomes At the time of writing, three patients were successfully treated with ONCOS-102 a total of 18 doses of OV with no transmission of virus between staff or patients. There has been no incidence of peritonitis, local infection, or catheter dislodgement. Nurses have been able to administer the OV with confidence and without adverse events related to the administration procedure or inadvertent exposure. Nurses verbalized comfort in caring for patients receiving OV in the ambulatory setting via this mode of administration. Discussion Nurses are instrumental in ensuring the safety of staff and patients. As novel oncology treatments emerge, the role of the nurse in establishing standards becomes even more important, but not without challenges. The implementation of IP OV therapy is a true exemplar of why nursing involvement is critically important at the initiation of a new clinical trial. Without it, safety processes and policies may not be established in a timely fashion or adverse events may occur from the absence of these systems being in place. With new treatments, there is little to no evidence to guide what measures should be implemented. In the absence of this, nurses must utilize expert opinion and similar clinical precedent to determine what constitutes adequate protection of staff, patient, and environment. The measures established in this institution’s policy were based on those used for T-VEC administration,6,10 universal biohazard precautions,11 and internal experts in employee safety and IF measures. Exposure of staff and other patients to viral shedding and subsequent infection was theoretically possible; however, there have been no reported cases of infection in household members of a patient treated with OV.12 However, there have been accidental exposures of health care personnel while handling T-VEC, such as needlestick and eye exposure.10 Aside from requiring treatment with antiviral medication, serious sequelae do not seem to have been reported in these known exposures.10 Nonetheless, vigilance in transporting the OV, handling spills, cleaning of environmental surfaces, and disposal of waste contaminated with OV is essential to reduce risk.12 In the absence of clear
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safety assurances, there can be a degree of uncertainty regarding how conservatively to proceed regarding IF measures, and as such policies were developed with an abundance of caution. It will be necessary to re-evaluate these measures as OV become more prevalent and more research is available. As an example, a decade ago T-VEC had to be administered in a negative-pressure room in the United Kingdom, but now can be safety given in a standard ambulatory setting.10 Another decision that had to be made was regarding the length of time patients treated with ONCOS-102 were required to maintain safety precautions. In the initial phase 1 study of 12 patients, infective viral particles were found in the urine and saliva of one patient and in the saliva only of two patients 3 days after dosing.13 However, ONCOS102 had been administered intravenously in these patients; patients in which ONCOS-102 had been given intratumorally did not have any samples with viral particles.13 Whether viral particles were found at further time points was either not studied or not reported. It was unknown whether viral particles would be found in the body fluids of patients who received IP ONCOS-102, and for how long after treatment. Another question not addressed was whether these viral particles were potentially infective. Although it was difficult to find evidence for how long treated patients should be maintained on safety precautions, a lack of evidence does not equate to a lack of risk to others. It is recommended from this experience to consider the four interrelated topics described when developing a nursing policy for a novel agent and process. What appeared to be a simple need to create a policy for the administration of an OV resulted in a careful look at the health care system and coordination of departments outside of nursing. Office administration and patient scheduling had to be aware of the need for early morning appointments. The medical team had to also be available early in the day, and be aware to see the patient in the infusion room, not in the clinic. Pharmacy had to reserve personnel and hood time for the reconstitution of the viral drug. Institutions who require a similar policy should map the path of both the OV agent and that of the patient to determine where coordination with other departments is required. Questions that should be asked could be: What is that department’s workflow and how would the new policy impact them? What education would be required? How would this education be delivered, or how would staff obtain the information needed to provide optimal patient care? Such questions should be addressed before the first patient is treated. Conclusion The infusion of OV treatment via an IP catheter was an unfamiliar administration approach requiring skillful collaboration involving many stakeholders. In this case, it was led by nursing to ensure patient and staff safety, regulatory alignment, as well as unit
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readiness. It was imperative that nurses from clinical trials, infusion, and leadership jointly develop this policy to ensure successful implementation. We strongly recommend that nursing be involved at site initiation of a new clinical trial. Nurses at institutions who are considering the use of OV in clinical trials should first determine whether a new nursing policy needs to be developed and whether the administering nurses will require additional education. If so, carefully consider the non-nursing departments that should be aware and involved, such as IF, pharmacy, and environmental services. Staff that will be responsible for administering the OV product should be fully educated on techniques and risks. Patients should be educated as well, per protocol informed consent and recommendations; any dressings and facility-specific requirements for IF should be reinforced by nursing staff. Efforts continue in evaluating safety measures and revision of standards as we receive more knowledge from these clinical trials. Early nursing involvement and inclusion of multidisciplinary hospital departments facilitated the creation of a nursing policy that maintained fidelity to the research protocol and minimized potential risk to nursing staff. References 1. Jhawar SR, Thandoni A, Bommareddy PK, et al. Oncolytic viruses natural and genetically engineered cancer immunotherapies. Front Oncol. 2017;7(202). 2. Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol. 2007;4:101–117. 3. Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene Iaherparepvec: first in class oncolytic virotherapy. Hum Vaccin Immunother. 2018;14:839–846. 4. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. 5. Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66:1249–1264. 6. Wall LM, Baldwin-Medsker A. Safe and effective standards of care. Clin J Oncol Nurs. 2017;21:E260–E266. 7. Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3:841–849. 8. Bujis PRA, Verhagen JHE, van Eijck CHJ, van den Hoogen BG. Oncolytic viruses: from bench to bedside with a focus on safety. Hum Vaccin Immunother. 2015;11:1573–1584. 9. Centers for Disease Control and Prevention. Recognizing the biosafety levels. Available at: https://www.cdc.gov/training/QuickLearns/biosafety/. Accessed 13 June, 2019. 10. Harrington KJ, Michielin O, Malvehy J, et al. A practical guide to the handling and administration of talimogene laherparepvec in Europe. Onco Targets Ther. 2017;10:3867–3880. 11. Broussard IM, Kahwaji CI. Universal precautions [Updated March 16, 2019]. StatPearls. Treasure Island. FL: StatPearls Publishing; 2019. https://www.ncbi.nlm.nih. gov/books/NBK470223/. Accessed 4 June 2019. 12. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–662. 13. Ranki T, Pesonen S, Hemminki A, et al. Phase I study with ONCOS-102 for the treatment of solid tumors an evaluation of clinical response and exploratory analysis of immune markers. J Immunother Cancer. 2016;4:17.