Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review

Background Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. Objective The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. Methods This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a “physiologic range” to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. Results This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. Conclusions The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. International Registered Report Identifier (IRRID) PRR1-10.2196/38167

ZCA1 RTRB-R (O2) CONSTANCE, J with leukemia. Hypothesis 1: Interpatient variability in opioid exposure will exceed 50% due to inherent metabolic differences, disease status, and treatment-related pharmacokinetic alterations. Specific Aim 2: In leukemic cell lines, changes in response to chemotherapy based on leukemic subtype and µOR function will be determined. Hypothesis 2: Clinically-experienced concentrations of opioids will change chemotherapeutic response in different leukemic subtypes corresponding with µOR function by >25%. Specific Aim 3: In patients with leukemia, the frequency of opioid-chemotherapy DDIs based on clinical and molecular factors will be determined. Hypothesis 3: Clinical and molecular features associated with opioid-chemotherapy DDI conferring chemotherapy resistance are present in >20% of patients prescribed opioids. Understanding the impact of µOR activity on chemotherapeutic response across similar but biologically distinct leukemia cell types will provide new insights into mechanisms underlying drug resistance, relapse, or non-response and drive precision medicine in opioid prescribing. This application will provide key preliminary data to support an NIH R01 aimed at predicting altered chemotherapeutic response due to supportive care medication exposure among patients undergoing treatment for leukemia.

PUBLIC HEALTH RELEVANCE:
It is desirable to avoid detrimental drug interactions to ensure each patient achieves the best possible response to their chemotherapy. The goal of this research application is to determine the impact of opioid-chemotherapy interactions on chemotherapeutic efficacy in blood cancer.

CRITIQUE:
The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that critiques and criteria scores, prepared prior to the review meeting, may not have been revised following discussions at the meeting. The "Resume and Summary of Discussion" section summarizes the final opinions of the review committee.

Overall Impact
This re-submission comes from a highly-qualified candidate, who is currently a research assistant professor in the Department of Pediatrics at the University of Utah School of Medicine who has a focus on pediatric oncology research. The candidate is productive, has institutional support for an independent research career and has an excellent career development plan with a Career Advisory Team. Although no major weaknesses were noted, some limitations include the need for more epidemiology and applied biostatistics in the research plan and a clear plan for how the current study that embraces variability will provide key evidence for the next R01.

Strengths
• High quality training: PhD in pharmacology and toxicology (published 7 articles from dissertation), training in molecular biology, and board certified in clinical pharmacology.
• Productive throughout PhD training and post-doctoral training (>30 publications) and runs a translational research program since 2015 supported in part by internal institution funding. • Seeks to get advanced training in phospho-flow cytometry, pharmacometrics, the conduct of pharmaco-epidemiologic studies requiring very large data sets, and translational research in the setting of clinical management and care of patients with pediatric malignancies. The latter two training goals are very relevant and appropriate for translating his research to human populations, specifically in children, adolescents, and young adults (CAYA).
• Letters are strongly supportive of his research goals and indicate a willingness of the writers to continue to collaborate and work with Dr. Constance. The letter from the Chair of Pediatrics indicates a high confidence in an independent research career for Dr. Constance.

Strengths
• With one exception (see below), the scientific training goals, the composition of the Career Advisor Team, the timeline (3 years), and the career development activities (Research Investigator Certificate, Responsible Conduct of Research, Grantsmanship, External Advisors, Professional Societies, Huntsman Cancer Institute membership, Leadership) are all appropriate career goals.
• The candidate has built the Career Advisory Team (Drs. Deininger, Lemons, Lim, and Watt), whom he will meet with on a quarterly basis to discuss his research and career development progress as well as progress in achieving independent R01 research grant funding.
• The timeline presented in Table 2 is very reasonable with the first milestone (Aim 1) to be achieved at the end of the second quarter in year 2.

Weaknesses
• The candidate notes that the Greater Intermountain Node (GIN) Database Opioid Research Consultation (DORC) group monthly meetings will advance his knowledge of pharmacoepidemiology. Additionally, the candidate proposes to use the Intermountain Data Services for observational studies (see budget). There are extensive resources and expertise at UT, especially at the Huntsman, for epidemiology, pharmaco-epidemiology, study design, analysis and population science in general. If the candidate is serious about becoming a competent translational scientist in clinical and survivorship care, this seems like a missed opportunity. The candidate is encouraged to seek out these opportunities and capitalize on them. • (minor) The timeline presented in Table 2 has Aim 3 extending all the way to the end of year 3 (and beyond?). However, data from this aim may be critical for an R01 research grant application. What are the milestones/data acquisition and analysis that need to be completed before the end of year 3 for a robust R01 research grant application?

Strengths
• Drug-drug interactions (DDIs) are generally understudied in cancer treatment and the lack of such knowledge makes it difficult to optimize dosing of the drugs.
• The specific DDI of opioids and chemotherapy are relevant for CAYAs, but probably also for many adult cancers treated with chemotherapy (e.g., ovarian cancer), leading to a broader application of this work if successful.
• The availability of the biorepository of the scavenge blood samples for CAYA leukemia patients is a great asset to the project.
• Specific aims are clear and appear to be doable in the environment.

Weaknesses
• Variability can be helpful and hurtful in such a study. There are many level of variability present in this study: type of leukemia in human specimens; type of cell line; level of opioids in blood samples of CAYAs; whether the opioids augment or inhibit malignancy; repeated measures (Aim 3); etc. There can also be positive or negative correlations between all these sources of variability. While the candidate is correct in saying that this represents "real-world variability", it will also make it difficult get actionable next steps from the data/results that will translatable to the next step of research.

Strengths
• The candidate has established outstanding collaborators, who have relevant expertise and the Career Advisory Team that can help him with his research, as well as his career development.

Weaknesses
• An applied biostatistician or pharmaco-epidemiologist may enhance the project and the candidate training.

Strengths
• Access to a critical biorepository.
• Strong letter of support from the Department Chair of Pediatrics.
• Highly-supportive environment, as noted by the letters of collaboration and availability of services.

Protections for Human Subjects
Acceptable Risks and Adequate Protections • Human Subjects protections are in line with samples from a biorepository that fall under a waiver of consent.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Not Applicable (No Clinical Trials)

Resubmission
• Generally a responsive re-submission.

Acceptable
Comments on Format (Required): • IRB training; RCR course-part of a larger Research Investigator Certificate (RATS CRC course).
Comments on Subject Matter (Required): • Not specified but all courses were noted to meet University and NIH criteria.
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • On-going, informal training in RCR.
Comments on Duration (Required): • IRB training -online (unknown duration); RATS RCR course-part of a larger Research Investigator Certificate (unknown duration); Comments on Frequency (Required): • IRB training -online (every two years); RATS CRC course-part of a larger Research Investigator Certificate (every 4 years)

Resource Sharing Plans
Acceptable

Overall Impact
This applicant addresses an important topic, namely the interaction between opioids and chemotherapy effectiveness. The focus is on childhood, adolescent, and young adult (CAYA) cancer patients, for whom the frequency of opioid treatment is high. The studies leverage the professional strengths of the candidate and include population pharmacokinetics, mechanistic studies of drug-drug-interactions and interrogation of patient specimens for early translation. The training plan and research aims are wellintegrated. This is a very strong application, with likely clinically impactful results.

Strengths
• The candidate earned a bachelor degree in chemistry, followed by a Ph.D. in pharmacology/toxicology, and is a board accredited clinical pharmacologist.
• The applicant has both first-and senior-author publications studying opioids in cancer patients, and has a substantial record of first authored papers focused on leukemia chemotherapy and polypharmacy. Expertise in pediatric cancers has also been demonstrated.
• The highly productive postdoctoral period yielded 15 first authored papers and numerous collaborative works, indicative of the strong interdisciplinary environment.
• The applicant has received institutional investments, including 90% release for research and a KL2-type institutional training award.

Strengths
• The candidate will be committed 90% to research, and has identified a strong plan that includes training, mentorship, research, and professional development activities.
• A research scholarship program for external mentorship complements an outstanding mentoring team within the organization.
• Course-work in genomics, a focus of the research plan, is included.
• Leadership training plans are outlined, including a principal investigator certification plan.
• Formal annual evaluation is outlined, as well as a plan for transitioning to independent funding.
• A specific, measurable plan for manuscripts and a detailed timeline are included.
• RCR training is addressed well.

Strengths
• The applicant is responsive to previous concerns about the research plan.
• The applicant documents the prevalence of opioid use, making a strong case for the importance of population PK measures to establish physiologically-relevant doses.
• The aims are independent, because physiologic ranges can be approximated from early in the study.
• In a cell-based study, ~10 cell lines with various traits, all derived from leukemia, will be tested for chemosensitivity with and without opioid exposure, considering mu-opioid receptor expression as a mediator. High-throughput screening assays will be employed, which have ancillary training benefits.
• The research aims are well-integrated with training aims.

Strengths
• The consultants and collaborators include a hematologic oncologist, a pediatric oncologist, a cancer biologist, and a pharmacologist, all of whom provide meaningful letters of support. The expertise is complementary and an annual plan for formal evaluation by this group is built into the training plan.

Strengths
• The institution is strong and well-suited to the applicant's research focus area.
• The availability of strong interdisciplinary collaborators relevant to the project speaks to the institutions strength in the area of research.
• The institutions has demonstrated investment, both in release time and in the awarding of the KL2-like training mechanism.

Resubmission
• Very responsive to previous concerns.

Acceptable
Comments on Format (Required): • Formal course-work is included.
Comments on Subject Matter (Required): • All relevant content areas are included.
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • The applicant has detailed plans for participation.

Comments on Duration (Required):
• Throughout training award.

Resource Sharing Plans
Not Applicable (No Relevant Resources)

Overall Impact
This is a resubmission of a K22 career development grant from Dr. Jonathan Constance, who is a board accredited clinical pharmacologist, who proposes to address and important clinical research question using multiple analytical methods to understand detrimental opioid chemotherapy interactions on chemotherapeutic efficacy in blood cancer in children. The proposed research is important to determine the best possible response to chemotherapy. The application is well-written and highlyresponsive to the prior critique. Since the submission, he received a Primary Children's Hospital Foundation Career Development grant. He has also provided preliminary data for this research showing the opioids-induced resistance to molecularly-targeted chemotherapy, but the impact is dependent on the cancer type. This is an important question, and it what is learned from this study could be important for adult-onset cancers. His research methods are novel and the clinical translation is important. His letters are very strong, and attest to his knowledge of the field and his trajectory as an independent researcher.

Strengths
• Dr. Constance has received outstanding training as a pharmacologist, and completed a postdoctoral fellowship in clinical pharmacology (board accredited) and completed a fellowship in pediatric clinical pharmacology (relevant to this application).
• He was accepted to the American College of Clinical Pharmacology Inaugural Leadership Development Program, received a Center for Clinical and Translational Science and Primary Children's Hospital Foundation Career Development Award, and was selected as the Vice President's Clinical and Translational Research Scholar. These awards attest to his trajectory to be a successful and independent investigator.
• Candidates letters are outstanding.

Weaknesses
• It was mentioned in the prior review that the candidate lacked publications (first-author) on the topic of this application, and this was not addressed in the introduction. It would have been good to see an explanation. He does have 2 publications on the topic but in one (Leukemia and Lymphoma) he is last author (not senior), and the other published in Clinical Translational Science he is a middle author.
• He was co-author on the 2 papers (2020 and 2021) and nothing between 2020 and 2017. However, the papers in 2017 he is first-author and they are relevant to the topic of this application.

Strengths
• Dr. Constance has a clear training and career path outlined. He proposes to include training in advanced methods in phospho-flow cytometry, pharmacometrics, pharmaco-epidemiologic methods using large data sets, and translational research in the setting of clinical management and care of patients with pediatric malignancies. These skills will be important for his transition to independence.
• He also proposes to participate in other work-shops and leadership programs.
• His mentors are all willing and available to continue mentoring.

Strengths
• The candidate proposes three specific aims to test his central hypothesis that chemotherapy response will change with clinically-relevant concentrations of opioids. This research question is important and significant for improving patient outcomes.
• The concerns about clinical translation has been addressed.

Strengths
• Dr. Constance assembled 4 career advisors in complementary content areas (oncology, pediatric oncology, cancer biology, and pharmacology). All are supportive to work with Dr. Constance and the letters are excellent in showing their support.
• He uses multiple approaches to test this hypothesis, including use of cell lines.

Strengths
• There are no concerns regarding the commitment of University of Utah to support the candidate and the environment is excellent for Dr. Constance to complete the work proposed.
• Dr. Giardino, Chair of Pediatrics at the University of Utah writes a very strong support letter, confirming 75% protected research time to conduct the research in this K22 career development award.