Immune checkpoint inhibitors (ICIs) have improved survival in multiple cancer types. To date, there are multiple ICI classes approved, targeting CTLA-4, PD-1, PD-L1, and LAG-3.1 However, ICIs can induce immune-related adverse events (irAEs) against host organs, spanning a wide clinical spectrum ranging from asymptomatic to severe.2 All of the national and international societies, including ASCO,3 NCCN,4 the Society for Immunotherapy of Cancer (SITC),5 and ESMO6 have released guidelines specific to irAE management. However, these general guidelines are limited in terms of multidisciplinary management of difficult and complex irAEs for which prompt diagnosis and treatment are critical to reverse toxicity, resulting in a substantial impact on the patient’s options and timing for future cancer therapeutics. We present our institutional experience with the formation of the MD Anderson Cancer Center (MDACC) Immuno-Oncology Toxicity (IOTOX) initiative, which is led jointly by the Divisions of Internal Medicine and Cancer Medicine to standardize and expedite irAE diagnosis and management, disseminate best practices, and facilitate IOTOX research to improve patient outcomes.
Rationale for IOTOX Initiative and Working Group Development
The rapidly increasing demand and urgent need for prompt and effective management of irAEs has been recognized as an operational priority at MDACC. In 2022, there were >4,500 unique patients receiving an ICI at our institution. Based on ICI order trends, we project a 30% increase in the number of patients receiving ICIs by 2025 (Figure 1). Using Natural Language Processing (NLP) methodology of electronic medical record (EMR) notes, we estimated that approximately 5,000 IOTOX cases sought toxicity management at MDACC in 2022, reflecting a rapid increase in the volume since the establishment of the initiative in 2019 (Figure 2). Historically, significant variation in IOTOX management, clinical workflows, and referral patterns across departments limited the quality and effectiveness of services provided. To overcome these operational inefficiencies, the IOTOX initiative was launched, and IOTOX clinical care, research, and education were designated as an institutional priority. An intranet website accessible to MDACC employees was developed for quick access to IOTOX-related information and tools (Figure 3).
The annual number of patients who received ICI treatment at MD Anderson from 2010 (blue bars), along with the corresponding percentage increase compared with the previous year. Additionally, projected patient numbers for ICI treatment from 2023 to 2025 are presented based on a forecasting model (orange bars).
Abbreviation: ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2023.7119
The distribution of IOTOX case numbers at MDACC in 2019 and 2022, categorized by organ toxicity. Each bar represents a specific toxicity case count.
Abbreviations: GI, gastrointestinal; IOTOX, Immuno-Oncology Toxicity initiative; MDACC, MD Anderson Cancer Center.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2023.7119
A timeline of MDACC’s IOTOX initiative efforts, encompassing clinical, educational, and research activities.
Abbreviations: IOTOX, immuno-oncology toxicity; ITOP, IOTOX Operational Platform; MDACC, MD Anderson Cancer Center.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2023.7119
This article discusses the key deliverables of the IOTOX initiative.
Standardizing IOTOX Clinical Practice
MDACC IOTOX Guidelines
Due to the lack of standardized practices, the novelty of irAEs, and subtle differences in presentation and treatments compared with their spontaneous autoimmune counterparts, standardization of IOTOX management guidelines is key to delivering the best possible care to patients (Table 1). Each organ site subspecialty developed decision pathways for diagnosis and treatment based on the available evidence and institutional expertise (Table 2). The guidelines were posted on the MDACC intranet in a familiar institutional format for ease of interpretation. The algorithms that received approval from the Clinical Effectiveness Office have been made available for public access on an external website (https://www.mdanderson.org/for-physicians/clinical-tools-resources/clinical-practice-algorithms/clinical-management-algorithms.html). It is important to note that these guidelines incorporate complex and refractory irAEs that are specific to the unique patient population at a tertiary cancer center such as MDACC. Therefore, they generally include a more aggressive and comprehensive approach compared with the current oncology society guidelines, which are more customized to community oncology practice. As the peer-reviewed evidence base grows in support of these management strategies, the goal is to publish the MDACC IOTOX management guidelines as a broader reference.
Summary of MDACC IOTOX Clinical Resources
MDACC IOTOX Algorithms and Guidelines
MDACC IOTOX Guideline Web App
MDACC clinical providers can access IOTOX patient management recommendations on a web application available in the MDACC web app store or on an MDACC authorized computer. This allows providers to easily access and review the relevant publications and references to support patient recommendations. These recommendations are reviewed on an annual basis and all updates to guidelines and our national algorithms can also be found on the IOTOX web application.
MDACC IOTOX Wallet Card
As a tertiary referral center, many of our patients live far from the institution and may need to seek emergency care outside of MDACC. To better equip patients and their community providers with a foundation of information, we developed wallet cards that include the patient’s name, cancer diagnosis, immunotherapy class, specific immunotherapy name, date of immunotherapy initiation, and oncology contact information. In addition, a simplified summary regarding the most common irAE symptoms is included on the cards, so that the affected patient and outside clinical providers have quick access to potential symptoms. The card design is based on the Oncology Nursing Society’s Immunotherapy Patient Wallet Card, with modifications specific to MDACC patients.7
MDACC Epic Clinical Optimization Tools
Diagnostic Codes
The clinical standardization also includes tracking and billing for appropriate activities resulting from irAEs. These activities often do not have established billing codes, or those that exist are too broad and nonspecific for organ systems. Therefore, each subspecialty identified a list of billing codes most frequently used for irAEs and linked irAE-specific symptom codes with general codes for IOTOX or cancer therapy toxicity as a bundled package. These billing code bundles will allow for tracking irAE-related consults and generation of patient lists based on these discrete billing codes within the EMR.
Smart Order Sets (Ambulatory and Inpatient)
To address the inconsistency of evaluations across providers, a standardized diagnostic workup package was developed by creating IOTOX organ-specific smart order sets within our EMR. The specific evaluation items were proposed and reviewed by each subspecialty expert. To avoid duplicate workup, the overlapping laboratory studies among different irAEs were listed up-front in the general evaluation section for any suspected irAE, followed by additional order sets specific to the involved organ system. Laboratory, imaging, biopsy requests, and specialist referrals are all included in IOTOX smart order sets. In addition, a separate group of order sets was developed for the inpatient setting because the type and severity of irAEs can differ from the ambulatory setting.
Standardized Documentation in Referral Request and Clinical Encounters
To help streamline immunotoxicity documentation information to be readily accessible, the EMR was leveraged to autopopulate IOTOX-specific referral requests and smart phrases (toxicity grading and toxicity referral note template), thereby decreasing the need for tedious searches across different sections of the EMR and allowing for more streamlined clinical encounters. For clinics with a higher volume of IOTOX patient referrals, we developed Express Lanes in the EMR that include the prebuilt diagnosis/billing codes, order sets, and standard IOTOX smart phrase note template with one click.
Education Resources to Providers and Patients
IOTOX Annual National Clinical Education Symposium
As part of the institutional IOTOX initiative, we aim to share best practices with the broader oncology community (Table 3). To achieve this, we organized an annual symposium to present the MDACC IOTOX guideline recommendations and collaborate with external experts and leaders of national societies (NCCN, ASCO, ESMO, and SITC) in the clinical management of IOTOX. The hybrid event facilitates the discussions on the diagnosis and management of patients with irAEs, featuring clinical presentations and case discussions led by health professionals from MDACC and invited expert guest speakers. Our goal is to foster an informative exchange and contribute to advancements in the rapidly evolving field.
Summary of MDACC IOTOX Education Resources
IOTOX Epic Tool Training Session
To teach our providers about the availability and use of Epic IOTOX tools, we have implemented a regularly scheduled training program. This approach incorporates a monthly rotation of educational materials, thereby promoting continuous learning and skill development. This knowledgeable and proficient base of providers are well-equipped to use the IOTOX tools optimally.
IOTOX Handbook
To further disseminate information on management of irAEs, in September 2022, IOTOX specialists from MDACC published the first immunotherapy toxicity practice handbook that is publicly accessible. The handbook is composed of 15 chapters focusing on the comprehensive, systematic, and clinical review of toxicities and toxicity management across organ sites.8 The organ sites covered include the endocrine system, eye, gut, heart, kidney, liver, lung, musculoskeletal system, nervous system, pancreas, and skin, as well as the inclusion of perspectives from anesthesiology, infectious disease, and pathology. The contributors are a group of experts offering routine clinical care to patients with the most complex and refractory IOTOX conditions, conducting pioneering research, and providing guidance for clinical practice to peers and trainees in the field.
IOTOX Monthly Guideline Education Lecture Series
To achieve the goal of standardization of irAE management, we developed a regular lecture series on specific irAEs led by organ-system experts within individual internal medicine subspecialties and oncology departments. These lectures also educate new rotating trainees and advanced practice providers, who are often the first point of contact for patients, and ensure that management strategies are up-to-date with the rapidly expanding immunotoxicity literature.
IOTOX Website
To centralize the broad and diverse communications pertaining to MDACC’s efforts with IOTOX, we developed a website offering comprehensive information about IOTOX initiative–related activities. The website hosts a wide array of resources for internal users covering clinical, research, and educational aspects. These resources include flyers, detailed event information, recorded IOTOX presentations, an FDA-approved ICI drug list, and other relevant items.
IOTOX Patient Education Materials
To increase awareness and early recognition of irAEs, patients must be aware of the possible side effects and their presenting signs and symptoms before ICI initiation. To aid understanding, we developed patient education brochures describing typical irAEs observed in each organ system. The brochures are provided in both printed handouts and online format. Patients can access the brochures at any time and use them as quick and easy references with instructions of when to contact their treating physicians or seek emergency care upon symptom onset.
IOTOX-Related Research
IOTOX Annual Research Retreat
To broadly disseminate our clinical, translational, and basic science IOTOX research (Table 4), we hold an annual research retreat featuring investigators at MDACC and keynote speakers (often external) who are experts in IOTOX research. They are invited to set the stage and provide updates in their areas of expertise. Following the keynote speaker’s presentation, panel discussions with audience interaction address broader questions and debates in the field of irAEs. A poster session is scheduled after the oral presentations to engage discussions, foster interactions between faculty and trainees, and promote collaborations during the retreat.
Summary of MDACC IOTOX Research Resources
IOTOX Databases
A database of recently published articles by MDACC faculty was established to track research in the IOTOX space. Publications are tracked as a metric demonstrating growth and success over time. The publications are organized by organ site when feasible. The database can also be accessed and used as a resource for literature reviews and background information for grants and manuscripts.
A database to collect information on research studies being conducted by MDACC faculty was created to track protocols across departments investigating irAEs as a main outcome. This database can be used by MDACC employees to identify potential protocols for their patients and review active protocols prior to designing a new study to ensure there is no overlap with research efforts from other departments.
IOTOX Operational Platform
Improving patient outcomes requires better understanding of biologic mechanisms and predictors of IOTOX, as well as optimizing treatment algorithms. To achieve this goal, the IOTOX Operational Platform (ITOP) was developed as an institutional infrastructure initiative to enable collection of longitudinal and quality-controlled biospecimens. The ITOP initiative leverages the high volume of patients treated with ICIs at MDACC, clinical and research IOTOX expertise, and infrastructure for data management and biospecimen collection in order to streamline IOTOX research by MDACC investigators.
IOTOX Research Seminar Series
Research from MDACC and collaborators outside of the institution is highlighted at the monthly research seminar series. Faculty and trainees present new research concepts, ongoing projects, and recently published work to provide a comprehensive view of the broad range of research being conducted. To achieve this, presentations are limited to 15 minutes followed by a 15-minute question and answer session. The goal of bringing such a wide range of expertise to the seminar is to foster discussion and potential collaborations for IOTOX research. We aspire to use this forum to develop research teams and questions for future grant applications.
Conclusions and Future Directions
The MDACC IOTOX initiative was established in response to the growing incidence of irAEs as ICIs become more widely disseminated in practice and combination ICIs continue to emerge. Our strategy is based on 3 key pillars: (1) improving clinical effectiveness, (2) advancing education, and (3) conducting innovative research (Figure 4).
The future directions of MDACC’s IOTOX initiative will advance across clinical, educational, and research dimensions.
Abbreviations: IOTOX, immuno-oncology toxicity; MDACC, MD Anderson Cancer Center.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2023.7119
Clinical Effectiveness
We are pursuing our goal of standardizing IOTOX clinical practices by assessing the implementation of IOTOX guidelines via patient outcomes as an integral part of our future directions. Our aim is to make all 14 guidelines publicly available within the next 3 years to share our practice experience at MDACC with the goal of benefitting patients on a global scale. To enhance accessibility for health care providers, we developed the MDACC IOTOX guideline web app, available in the MDACC app store and on MDACC authorized computers. This user-friendly web app serves as a convenient reference tool, providing the IOTOX guidelines for easy access. We are currently in the process of expanding this app to institutions within the MDACC Cancer Network, which consists of 6 cancer centers across the country. Our plan is to also make it available to all interested external clinical providers at the next stage. To further streamline the clinical daily workflow, we established express lanes by integrating consult note templates, CTCAE measurement tables, and patient education materials into the smart order sets. These efforts are supported by the development of an advanced practice provider–led triage clinic for IOTOX and the creation of a centralized inpatient service for all patients, led by hospitalists. These measures ensure a robust multidisciplinary approach consistent with IOTOX guidelines, while also maintaining standardized treatment guidelines and improving clinical tools and workflow. As part of the assessment for the impact of these clinical practice changes, our quality improvement project has already demonstrated improved outcome of patients with immune-mediated colitis after implementing the MDACC practice guideline.9 Future endeavors include expanding our knowledge to the community. We envision that the standardized clinical data collection will enable dissection of the heterogeneity of these irAEs and development of novel clinical classifications to tailor therapeutic approaches.
Education
We have employed a multifaceted approach to educate our providers and patients about toxicity guidelines and toolsets, including monthly IOTOX education lecture series, patient education materials, the publication of an IOTOX handbook, Epic tool training sessions, regular updates to our comprehensive IOTOX website, and an annual national clinical education symposium on IOTOX. We are deeply committed to sharing our resources with the extended oncology communities on both a national and global scale. This mission has been launched by institutions within the MD Anderson Cancer Network nationwide. As part of our next stage plan, we aim to expand it beyond the MD Anderson Cancer Network to include all academic centers that are interested. To broaden our scope, we are intensifying our patient education efforts by launching a publicly accessible patient education webinar. In addition, with our expertise and patient volumes, we recognize our responsibility to train the next generation of IOTOX leaders nationwide and globally. Therefore, we propose to create a comprehensive educational program to empower trainees, junior faculty, and visiting faculty with IOTOX knowledge and skills.
Research
The ITOP research initiative consolidates the resources of MDACC to bear standardized data and biospecimen collections and pathology interpretation. We propose to link this research infrastructure to our ongoing programs, including the Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) program and the immunotherapy platform that efficiently analyze the biospecimens to accelerate research-driven patient care. The ITOP will serve as the foundation for studies exploring the fundamental mechanisms of irAEs, including their heterogeneity within organ sites to foster the identification of novel predictive biomarkers to optimize patient selection for ICIs. We continue to actively track IOTOX publications by MDACC faculty, and have established an IOTOX clinical trial database to promote and facilitate internal collaborations. To stay abreast of the latest research findings and foster both internal and external collaborations, we organize monthly IOTOX research seminar series and an annual research retreat. These platforms offer invaluable opportunities for learning and knowledge exchange of IOTOX research progress.
By intensively investing in clinical effectiveness, education, and clinical and translational research, we will achieve our goals of maximizing efficacy and minimizing ICI toxicity to improve outcomes in our patients with cancer.
Acknowledgments
We would like to acknowledge the IOTOX Initiative sponsors David Tweardy, MD, Division of Internal Medicine; Christopher Flowers, MD, the Division of Cancer Medicine; and Ignacio Wistuba, MD, Department of Translational Molecular Pathology, for their advice and guidance on the milestones we accomplished and vision for the future direction. We acknowledge all IOTOX leads from different specialties across the institute for their invaluable contributions in ensuring the availability of resources essential to the success of IOTOX initiatives.
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