J Cancer Surviv DOI 10.1007/s11764-014-0362-6

Seamless integration of clinical care and research in an innovative fertility preservation program: the Colorado Oncofertility Program model Kiara Blough & Chanel Mansfield & Laxmi A. Kondapalli

Received: 17 February 2014 / Accepted: 6 April 2014 # Springer Science+Business Media New York 2014

Abstract Purpose The purpose of this study is to describe a model of care for fertility preservation (FP) that integrates clinical care and research through the establishment of the Colorado Oncofertility Program’s (COP) patient registry. Methods To integrate research and clinical care, the COP developed a multidisciplinary organizational structure and established a prospective registry of demographic information and clinical data of patients who agree to participate in future studies. Results The patient registry allows for the integration of clinical care and research as well as streamlined data collection. Since the program launch in January 2012, over 285 patients have been evaluated and >95 % of approached patients have agreed to participate in the registry. Data collected are used for research, systematic program evaluation, and utilization of services. Implications for Cancer Survivors As one of the fastest growing oncofertility programs in the country, there is great potential for the COP’s registry to contribute to expanding the limited body of literature on the late effects of cancer treatment on fertility and reproductive health in the adolescent and young adult (AYA) oncology population. With the use of web-based bioinformatics, objective data are captured for clinical care, future studies, program evaluation, and quality assurance, without compromising patient autonomy, privacy, and confidentiality or the commitment to personalized care. K. Blough : C. Mansfield Department of Obstetrics and Gynecology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA L. A. Kondapalli (*) Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Colorado Denver Anschutz Medical Campus, 12700 East 19th Avenue, Mail Stop 8613, Aurora, CO 80045-0508, USA e-mail: [email protected]

Keywords Clinical research . Fertility preservation . Medical informatics

Introduction There are currently 14 million cancer survivors who will celebrate another birthday this year, of which, 10 % are under the age of 40 years old [1]. Cancer survivorship for this population has increased dramatically in the past 20 years largely due to advances in cancer therapeutics [1]. In the wake of these advances, factors contributing to survivor’s long-term quality of life are gaining importance. Future fertility is one such factor; however, limited research suggests that some therapeutics can be toxic to reproductive organs and impair future childbearing [2, 3]. A better understanding of the impact of cancer treatments on fertility and reproductive health is imperative to providing comprehensive care and improving quality of life in survivors. Oncofertility is a burgeoning subfield of medicine that bridges oncology and reproductive health. The Oncofertility Consortium is a national interdisciplinary initiative that has increased awareness of fertility as a survivorship issue and has spearheaded the translation of bench science to clinical care to improve methods of FP [4]. The field of oncofertility has evolved beyond merely FP and advocates a comprehensive approach to reproductive health for cancer patients and survivors. In accordance with this mission, the goal of the Colorado Oncofertility Program (COP) at the University of Colorado is to ensure that every young adult cancer patient receives timely and accurate information about his or her options for FP, thus empowering them to make informed choices about their reproductive futures within the context of their cancer treatment and survivorship care plan. In addition, the program strives to explore the long-term effects of cancer treatment for patients

J Cancer Surviv

and improve the overall quality of life for survivors. The program provides comprehensive reproductive care that extends beyond fertility. For instance, the team manages issues such as complex contraception, symptom management including sexual function and sleep disturbances, and late effects of treatment. Additionally, they provide preconception counseling and preimplantation genetic diagnosis (PGD) when patients are ready to conceive. One of the unique features of the COP is the direct integration of clinical care and research. Through the establishment of the patient registry, a database of clinical and research information, the program promotes the health of current and future patients through scientific activity.

Materials and methods In 2012, a comprehensive interdisciplinary team was established in which each member plays an integral role. The COP clinical team includes an oncofertility specialist trained in reproductive endocrinology and infertility, fertility nurses, embryologists, and clinical psychologists. The oncofertility specialist serves as the principal investigator for research studies. The research team includes medical trainees who conduct various research studies, a regulatory manager who ensures compliance with all regulatory boards and who also serves as an advocate for patients and research subjects, and a clinical study coordinator who is responsible for project management, manuscript preparation, participant recruitment, and the consent process. Patients are initially referred to the oncofertility clinic by an oncologist or treating physician. At the first point of patient contact, clinical care and research are integrated into the patient flow (Fig. 1). Upon referral, the initial consultation is scheduled within 24–48 h. It is imperative that consultations are scheduled promptly because cancer treatments are often time sensitive, and some FP techniques may require 2 weeks for females and 1–5 days for males. For inpatient referrals, all attempts are made to schedule inpatient consultations on the same day. While 71 % of these referrals come from the University of Colorado Cancer Center, 15 % are from the Children’s Hospital of Colorado and 14 % are from outside cancer centers throughout the Rocky Mountain region and the USA. Before their consultation, patients are contacted regarding their appointment and the new patient intake questionnaire Fig. 1 Clinical flow at the Colorado Oncofertility Program; BPA* best practice advisory

Patient receives diagnosis

BPA* reminds oncologist to refer to Oncofertility

that they will receive via email and a secure web link. Upon completion, intake forms are validated by electronic medical record (EMR) reviews. At the initial consultation, after a medical trainee conducts the history and physical, the clinical study coordinator recruits patients into the registry. To date, over 95 % of patients have consented to participate in the registry and to be contacted regarding future research. After informed consent is obtained, during waiting periods in the clinic, participants complete validated instruments on tablet computers. All self-reported information is collected from the patient at the time of consultation, thereby eliminating the burden for patients to report back to the COP. However, patients do consent to have their clinical information regarding medical history, course of treatment, and outcomes to be used for future oncofertility research. Therefore, clinical data continues to be collected by the study coordinator throughout the patient’s course of care. The oncofertility patient registry is managed through a Research Electronic Data Capture (REDCap) application [5]. REDCap is a secure, HIPAA compliant, web-based application design and allows for streamlined data collection and entry through web-based surveys. The registry was reviewed favorably by the Colorado Multiple Institutional Review Board (COMIRB) and approved under 45 CFR 46.110 and 21 CFR 56.110, expedited research categories 5 and 7. Patients 31 days to 100 years old are eligible to be included in the registry. Assent is obtained for those subjects aged 7–13 by signing an assent form along with their parent or legal guardian. Assent is not obtained for those under 7; however, their parent or legal guardian must sign the consent on their behalf. Assent is obtained from participants who are 13–17 by signing the consent form along with their parents, as this form is written at a level that is understandable to subjects of this age range. The patient registry has many components; the first of which is the new patient intake. This intake collects information regarding the patients’ demographics, medical history, present illness, and treatment and is used for clinical purposes. The intake is particularly important for patients whose records are not held within the institution’s EMR system. Additionally, for patients who elect FP, clinical outcomes, utilization rates, and pregnancy outcomes are collected. In addition to clinical information, the registry contains validated instruments that assess functional wellbeing (Functional Assessment of Cancer Therapy [FACT] [6]), sleep (Pittsburgh Sleep Quality Index [PSQI] [7]), and sexual dysfunction (Sexual

Consult scheduled within 24-48 hours of referral

Patient receives new patient intake via web link

Initial consultation patient recruited and consented for registry

Decision made whether to undergo FP; follow up scheduled as needed

J Cancer Surviv

Health Inventory for Men [SHIM] [8] and Female Sexual Function Index [FSFI] [9]). These instruments are used for research purposes and are only collected after informed consent is obtained. All patient identifiers and protected health information (PHI) are concealed within the database so that data is linked only to a unique ID. This de-identified data can be exported directly into a statistical program for analysis.

4%

3%

3% 2%

Other*

5%

24%

Testicular 8% Leukemia

Lymphoma Breast

20%

Patient Volume

21%

Ovarian Melanoma

18%

The Colorado Oncofertility Program established a database and patient registry that collects data for clinical care, current and future scientific investigation, program evaluation, and quality assessment. Additionally, the registry is used as a recruitment tool, as patients consent to be contacted if they are eligible for future studies. The existing dataset serves as the infrastructure for collaboration among students, mentees, and junior investigators. Using the data, investigators can explore a broad range of research questions. However, a protocol must be submitted to and approved by the COMIRB prior to data access or analysis. Studies that have stemmed from the registry have explored endocrine and metabolic profiles in cancer survivors, FP utilization and decisionmaking, and quality of life, sleep, and sexual health. With over 285 new patient consults since its inception in 2012, the COP is currently one of the highest-volume and fastest-growing FP programs in the country. Unique to the COP, reproductive care is provided to pediatric, AYA, and adult patients across both genders (68 % females vs. 32 % males). While the youngest patient included in the registry is an 18month-old female and the oldest patient is a 59-year-old male, the majority of patients are of reproductive age (Fig. 2). Patients receiving care have a broad range of diagnoses; however, the majority are lymphoma, breast cancer, leukemia, and testicular cancer patients (Fig. 3). To date, 20 patients have banked oocytes or embryos, and over 65 patients have banked sperm. Since the field of oncofertility emerged at the intersection of cancer therapy and reproductive medicine, FP is well-described for patients diagnosed with cancer, both pediatric and adult.

15%

10%

Male Female

5%

0% 0

Sarcoma Colorectal

12%

Results

Cervical

15

20

25

30

35

Age

Fig. 2 Patient volume by age and gender

41

46

57

Fig. 3 Cancer diagnoses * indicates other diagnoses including aplastic anemia, brain tumors, gastrointestinal cancers, sarcomas, systemic lupus erythematus, melanoma, neuroblastomas, prostate cancer, rheumatoid arthritis, thyroid cancer, and gender identity disorder

Currently, there are many established FP options for both females and males in addition to experimental techniques that are under investigation (Table 1). Since its launch in January 2012, the COP has reached many milestones. One important marker was launching the best practice advisory (BPA) within the institution’s EMR system. A BPA appears during patient intake for all new oncology patients under age 45. It asks if the provider has talked to the patient about their concerns regarding future fertility and/or if they are interested in FP. This ensures that all cancer patients are referred to the COP, are informed about the fertility risks of their treatment regimen, and are counseled regarding options for FP prior to undergoing treatment.

Discussion As a subfield of medicine, oncofertility is unique in that it primarily focuses on oncology patients within their reproductive years, specifically adolescents and young adults. The AYA oncology population is a group of patients who have long been underserved in the medical field. While advances in prevention, detection, and treatment of cancer have led to an overall improvement in survival rates, the survival rates for the AYA oncology population have remained relatively stagnant over the last decade [14–16]. As a result, the National Cancer Institute’s progress review group established recommendations to address the unique issues faced by the AYA oncology population [16] which, in 2012, resulted in a strategic plan proposed by the Livestrong Foundation [15]. The COP’s patient registry specifically addresses many of these recommendations including the following: strengthening and promoting advocacy and support of the AYA oncology patient, creating tools to study AYA oncology problems, and

J Cancer Surviv Table 1 Summary of current fertility preservation options FP method Established methods Embryo cryopreservation

Oocyte cryopreservation

Description

Special considerations

Hormonal stimulation of ovaries and collection of oocytes to create embryos using in vitro fertilization (IVF) methods. Resulting embryos are cryopreserved for future transfer Hormonal stimulation of ovaries and collection of oocytes with cryopreservation of unfertilized oocytes. Can be fertilized in the future to create embryos for transfer

▪ Must be postpubertal ▪ Need partner or donor sperm ▪ Established technique with thousands of live births ▪ Must be postpubertal ▪ Do not need sperm source ▪ IVF required upon thawing ▪ Several studies demonstrating live birth rates similar to using fresh embryos [10] ▪ Must be postpubertal ▪ Can be used for intrauterine insemination (IUI) or IVF ▪ Outpatient surgical procedure ▪ Can be used for IVF with intracytoplasmic sperm injection (ICSI)

Sperm cryopreservation

Cryopreservation of ejaculated sperm

Surgical sperm extraction

Percutaneous puncture and aspiration of sperm from the testis or epididymis

Experimental methods (performed under investigational protocol) Ovarian tissue cryopreservation Removal and cryopreservation of outer layer of the ovary (cortex), which contains immature oocytes

In vitro maturation (IVM)

Collection of immature oocytes without hormonal stimulation of the ovary

Immature testicular tissue cryopreservation

Surgical biopsy of testicular tissue from prepubertal males

increasing and improving survivorship-related research [16]. The COP's patient registry has the potential to make significant contributions to the limited body of research because, unlike many other clinical databases, it provides a comprehensive dataset comprising a broad range of cancer diagnoses and treatment regimens across age and gender. This allows for investigation of multiple long-term cancer outcomes in general, in addition to the ability to stratify and analyze outcomes by diagnosis and treatment. Current studies are specifically designed to describe late effects of cancer therapeutics to improve long-term quality of life. Scientific presentations have been made at national conferences in order to promote current research and progress being made in the field. Other oncofertility programs have described their programs and oncofertility models of care [17, 18]. In fact, Reinecke et al. conducted a comprehensive review of the nine Fertile Hope Centers of Excellence (FHCOE) programs and their collective strengths and weaknesses [19]. The COP shares many characteristics with the FHCOE programs including patient education and automated fertility notification procedures such as the BPA. In fact, many programs have

▪ Can be pre or postpubertal ▪ Outpatient surgical procedure ▪ Future uses include transplantation of thawed tissue or in vitro maturation of follicles and fertilization of oocytes ▪ Currently only option for prepubertal females ▪ 20 human live births from transplantation reported [10, 11 ]; none from in vitro maturation of follicles ▪ Must be postpubertal ▪ Case reports demonstrating viable embryos [12] ▪ One live birth reported [13] ▪ Currently only option for prepubertal males

implemented a systematic referral process in order to increase the likelihood that AYA oncology patients are appropriately referred to reproductive specialists [17, 19]. Reinecke et al. noted various weaknesses of the FHCOE programs, and recommendations for moving forward included a systematic way to analyze effectiveness of individual program components and complete systems [19]. The COP’s patient registry addresses these limitations by collecting data that allows for efficient and comprehensive program evaluation. Other registries capture data regarding oocyte cryopreservation and birth outcomes [20]. However, a unique feature of our program is the ability to prospectively collect data regarding cancer diagnosis and treatment across age and gender for patients undergoing all methods of FP. Additionally, the patient registry provides a longitudinal perspective throughout their care, collecting information before, during, and after treatment including FP outcomes. The patient registry not only integrates clinical care and research but also allows for efficient data capture and analysis. Each of the REDCap case report forms can be completed by study personnel or sent directly to

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patients via a secure web link and opened in survey interface for self-initiated data collection. Subsequently, study personnel validate self-reported data using EMR and the Colorado state tumor registry. Our data collection process reveals that patient-initiated surveys significantly improve the quantity and quality of collected data. Further, enhanced efficiency, minimal recall bias, and reduction of data entry by study personnel were noted. While the patient registry is a valuable resource, a primary limitation for use in research is the generalization of findings. Currently, participants are recruited from the COP, which may not be generalizable to a national population. For instance, 85 % of patients are Caucasian with only 7 % Hispanic. This limitation can be addressed as the registry expands and serves as the infrastructure for a multicenter collaboration among geographically diverse institutions. Another limitation to the patient registry is the accuracy of self-reported data collection, which is addressed through multiple methods of data validation including reviews of EMR and the Colorado state tumor registry.

Conclusion While the Colorado Oncofertility Program is in its nascent phase, it holds promise as a model that can be adapted to clinics serving a similar patient population, thereby functioning as a coordinating site for multiple study centers. This will allow for broader data collection and help ensure that the sample is nationally representative. With the infrastructure in place through REDCap, a web-based program, a national registry could be implemented efficiently and conveniently by granting controlled access to study personnel at other coordinating sites around the country or world. In addition to a national registry, future work will incorporate a biospecimen bank that is linked to clinical data. The goal of this registry is to create a sustainable source of highly objective data. We welcome collaboration with investigators and hope that our model of care will be replicated at other institutions. There are many opportunities for team science and collaboration with endocrinologists, oncologists, and other areas of discipline. Seamlessly integrating clinical care and research through the use of web-based bioinformatics has allowed the COP to uphold its values of patient autonomy, privacy, and confidentiality and its commitment to personalized care. Acknowledgments The authors would like to thank their colleagues in the University of Colorado Cancer Center including W. Thomas Purcell, MD, MBA, Associate Director of Clinical Services, who facilitated the establishment of the best practice advisory. Conflict of interest disclose.

The authors have no conflicts of interests to

Funding This study was supported by the National Institutes of Health’s Women’s Reproductive Health Research Award 5K12HD001271-13 (LAK) and the NIH/NCRR Colorado CTSI Grant UL1 RR025780.

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