Evaluation of a multilevel implementation program for timeout and shared decision making in breast cancer care: a mixed methods study among 11 hospital teams.

OBJECTIVE: Evaluation of a multilevel implementation program on shared decision making (SDM) for breast cancer clinicians. METHODS: The program was based on the 'Measurement Instrument for Determinants of Innovations-model' (MIDI). Key factors for effective implementation were included. Eleven breast cancer teams selected from two geographical areas participated; first six surgery teams and second five systemic therapy teams. A mixed method evaluation was carried out at the end of each period: Descriptive statistics were used for surveys and thematic content analysis for semi-structured interviews. RESULTS: Twenty-eight clinicians returned the questionnaire (42%). Clinicians (96%) endorse that SDM is relevant to breast cancer care. The program supported adoption of SDM in their practice. Limited financial means, time constraints and concurrent activities were frequently reported barriers. Interviews (n = 21) showed that using a 4-step SDM model - when reinforced by practical examples, handy cards, feedback and training - helped to internalize SDM theory. Clinicians experienced positive results for their patients and themselves. Task re-assignment and flexible outpatient planning reinforce sustainable change. Patient involvement was valued. CONCLUSION: Our program supported breast cancer clinicians to adopt SDM. PRACTICE IMPLICATIONS: To implement SDM, multilevel approaches are needed that reinforce intrinsic motivation by demonstrating benefits for patients and clinicians.

Effects and Working Mechanisms of a Multilevel Implementation Program for Applying Shared Decision-Making while Discussing Systemic Treatment in Breast Cancer.

Background: Enhancing the application of shared decision-making (SDM) is critical for integrating patient preferences in breast cancer treatment choices. We investigated the effect of an adapted multilevel SDM implementation program in breast cancer care. Methods: Breast cancer patients qualifying for (neo)adjuvant systemic treatment were included in a multicenter before−after study. Consultations were audio recorded between June 2018 and July 2019 and analyzed using the five-item Observing Patient Involvement in Decision-Making (OPTION-5) instrument to score SDM application by clinicians. The Shared Decision-Making Questionnaire (SDM-Q-9) was used to rate patients' perceived SDM level. Consultation duration, decision types, number of options discussed and consultations per patient were monitored. Regression analysis was used to investigate the correlated variables and program components. Results: Mean OPTION-5 scores increased from 33.9 (n = 63) before implementation to 54.3 (n = 49) after implementation (p < 0.001). The SDM-Q-9 scores did not change: 91.1 (n = 51) at baseline versus 88.9 (n = 23) after implementation (p = 0.81). Without increasing consultation time, clinicians discussed more options after implementation. The regression analysis showed that exposure to the implementation program, redistribution of tasks and discussing feedback from consultations was associated with a higher level of SDM. Conclusion: The multilevel program helped clinicians achieve clinically relevant improvement in SDM, especially when it is tailored to (individuals in) teams and includes (e-)training, discussing feedback on consultations and redistribution of tasks.

Ovarian tissue cryopreservation: Low usage rates and high live-birth rate after transplantation.

INTRODUCTION: The likelihood of survival after cancer treatment among young women with cancer has increased considerably, quality of life after treatment has drawn more attention. However, in young fertile women, fertility preservation is an important issue with regard to quality of life. One of the options of fertility preservation is ovarian tissue cryopreservation. The purpose of this follow-up study is to present our clinical experiences and evaluate the long-term follow up of ovarian cryopreservation to improve future patient selection. MATERIAL AND METHODS: From July 2002 to December 2015 at the Leiden University Hospital, the Netherlands, 69 young women underwent ovarian tissue cryopreservation when they were at risk of iatrogenic premature ovarian insufficiency. Follow-up data with regard to ovarian function were obtained until October 2018, from medical records and questionnaires. RESULTS: Of the 69 women in whom ovarian tissue cryopreservation was performed, 12 died (15.9%), 57 were approached to participate, of which 6 were lost to follow up. The indications for ovarian tissue cryopreservation were malignant (81.1%) and benign (18.9%) diseases in which gonadotoxic treatment was scheduled. In total, twenty women (39.2%) are known to have premature ovarian insufficiency due to gonadotoxic treatment. Fifteen women conceived spontaneously, and delivered 25 babies. In this cohort, the usage rate of autotransplantation is 8.7% (7/69). In total, nine autotransplantations of cryopreserved ovarian tissue were performed in seven patients (of which 1 ovarian tissue cryopreservation was performed in another hospital) after which 6 babies were born to four women, giving a live-birth rate of 57%. CONCLUSIONS: Ovarian tissue cryopreservation followed by autotransplantation is an effective method to restore fertility (live-birth rate of 57%). The usage rate of 8.7% (6/69) indicates that more knowledge about the risk of premature ovarian insufficiency after gonadotoxic treatment is needed to be able to offer ovarian tissue cryopreservation more selectively.

Ovarian survival after pelvic radiation: transposition until the age of 35 years.

PURPOSE: To evaluate the effectiveness of ovarian transposition (OT) prior to radiation therapy (RT) and to evaluate the effect of age on ovarian survival (OS) after OT. METHODS: We performed a retrospective control study, with women (aged < 45 years) who underwent OT prior to pelvic radiation, versus women diagnosed with cervical cancer and treated with hysterectomy/trachelectomy and radiation therapy. All women were treated between 1989 and 2010. The 5 years OS rate was calculated, with a sub-analysis for age (25-30; 31-35 and 36-40 years). Ovarian failure was defined as climacteric complaints (with or without starting hormone replacement therapy) and/or laboratory measurements (FSH > 40 IU/L and/or estradiol < 100 pmol/L), or bilateral salpingo oophorectomy. Women were censored at recurrence. RESULTS: Twenty-seven women after OT and 29 controls were included. The radiation dose was 44.8 Gy (25.0-63.0 Gy) and 46.3 Gy (45.0-50.0 Gy), respectively. The 5-year ovarian survival rate was 60.3% versus controls 0% (p < 0.001 95% CI 3.48-11.50). Despite the decrease in ovarian survival after OT with increasing age, in all age groups (25-30, 30-35 and 35-40) ovarian survival after OT was significantly better compared to women without OT (p = 0.001; p = 0.004 and p = 0.000, respectively). Neither intra-vaginal radiation therapy of concomitant chemotherapy in addition to pelvic radiation significantly altered ovarian survival. CONCLUSIONS: Our data shows that ovarian transposition prior to pelvic radiation is effective in women until the age of 35 years and needs to be discussed in patients aged 36-40 years.

Morphological and phenotypical features of ovarian metastases in breast cancer patients.

BACKGROUND: Autotransplantation of frozen-thawed ovarian tissue is a method to preserve ovarian function and fertility in patients undergoing gonadotoxic therapy. In oncology patients, the safety cannot yet be guaranteed, since current tumor detection methods can only exclude the presence of malignant cells in ovarian fragments that are not transplanted. We determined the need for a novel detection method by studying the distribution of tumor cells in ovaries from patients with breast cancer. Furthermore, we examined which cell-surface proteins are suitable as a target for non-invasive tumor-specific imaging of ovarian metastases from invasive breast cancer. METHODS: Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 46 women with primary invasive breast cancer and ovarian metastases. The localization and morphology of ovarian metastases were determined on hematoxylin-and-eosin-stained sections. The following cell-surface markers were immunohistochemically analyzed: E-cadherin, epithelial membrane antigen (EMA), human epidermal growth receptor type 2 (Her2/neu), carcinoembryonic antigen (CEA), αvß6 integrin and epithelial cell adhesion molecule (EpCAM). RESULTS: The majority of ovarian metastases (71%) consisted of a solitary metastasis or multiple distinct nodules separated by uninvolved ovarian tissue, suggesting that ovarian metastases might be overlooked by the current detection approach. Combining the targets E-cadherin, EMA and Her2/neu resulted in nearly 100% detection of ductal ovarian metastases, whereas the combination of EMA, Her2/neu and EpCAM was most suitable to detect lobular ovarian metastases. CONCLUSIONS: Examination of the actual ovarian transplants is recommended. A combination of targets is most appropriate to detect ovarian metastases by tumor-specific imaging.

Prevalence and Risk Factors of Ovarian Metastases in Breast Cancer Patients < 41 Years of Age in the Netherlands: A Nationwide Retrospective Cohort Study.

PURPOSE: Breast cancer is one of the primary indications for cryopreservation and subsequent autotransplantation of ovarian tissue. The safety of this fertility preservation method remains questionable, as the presence of disseminated breast tumor cells cannot yet be excluded in the ovarian autografts. We explored the prevalence of ovarian metastases among young breast cancer patients and determined risk factors for the development of ovarian metastases. METHODS: Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 2648 women with primary invasive breast cancer at age < 41 years in the period 2000-2010 in the Netherlands who subsequently underwent an oophorectomy. From this source population, all cases who had histologically confirmed ovarian metastases were included. For each case of whom clinical data were available, one control without ovarian metastases who matched the time interval between breast cancer diagnosis and oophorectomy was selected. Data were collected on patient characteristics, diagnosis, treatment and follow-up. RESULTS: Ovarian metastases were found in 63 out of 2648 patients who met the inclusion criteria. The risk of developing ovarian metastases increased with time passed since breast cancer diagnosis. Multivariate logistic regression analyses showed significant association between tumor stage and the development of ovarian metastases (p = 0.024). CONCLUSIONS: The prevalence of ovarian metastases was 2.4% among young breast cancer patients. Early ovary removal may reduce the risk of developing ovarian metastases. In breast cancer patients with tumors > 5 cm and/or inflammatory carcinoma, we recommend a cautious approach to ovarian tissue autotransplantation.

Feasibility and effects of a decision aid about fertility preservation.

This paper reports on the feasibility and preliminary effects of a decision aid (DA) about female fertility preservation (FP). We conducted a pilot multicentre randomized controlled trial of women with breast cancer aged 18-40 who were randomized to brochures or the DA. Over 18 months, 62 women were eligible, of which 42 were invited by their healthcare provider (74%) to participate in the study. A total of 36 women signed up for participation and 26 (72%) were randomized to brochures (n = 13) or the DA (n = 13). In both groups, many women (87%) read the brochures and eight women used all available brochures. In the intervention group, 7/13 women logged in to the DA. Women who received brochures had slightly less decisional conflict, whereas knowledge improved in both groups. Our results indicate that both brochures about FP and a detailed DA have beneficial effects with regard to knowledge, but the DA seemed to introduce slightly more decisional conflict (DC) than the brochures. Although we encountered challenges with recruitment, our design and measurements seem feasible and the effects of the information materials seem promising, hence justifying conducting a larger study.

Noninvasive Detection of Metastases and Follicle Density in Ovarian Tissue Using Full-Field Optical Coherence Tomography.

PURPOSE: Autotransplantation of ovarian tissue can be used to restore fertility in patients with cancer following gonadotoxic treatment. Whether this procedure is safe remains unclear, as current tumor detection methods render the ovarian tissue unsuitable for transplantation. Full-field optical coherence tomography (FF-OCT) is an imaging modality that rapidly produces high-resolution histology-like images without the need to fix, freeze, or stain the tissue. In this proof-of-concept study, we investigated whether FF-OCT can be used to detect metastases in ovarian tissue, thereby increasing the safety of ovarian tissue autotransplantation. We also evaluated whether cortical ovarian tissue and follicles remain viable following FF-OCT imaging. EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tissue samples were obtained from seven normal ovaries and fourteen ovaries containing metastases and/or micrometastases. These samples were deparaffinized and imaged using FF-OCT. The FF-OCT images were then compared with corresponding hematoxylin and eosin-stained tissue sections. Finally, we examined the effect of FF-OCT imaging on the viability of ovarian tissues and follicles in fresh bovine ovarian tissue using a glucose uptake and neutral red staining, respectively. RESULTS: FF-OCT illustrated both normal structures and metastases in ovarian tissue within minutes. Primordial follicles were readily identifiable. Finally, tissues and follicles remained viable following FF-OCT imaging for up to 180 and 60 minutes, respectively. CONCLUSIONS: FF-OCT imaging is a promising method for the noninvasive detection of metastases, including micrometastases, in ovarian tissue. Moreover, this method facilitates the selection of cortical ovarian tissue with the highest density of primordial follicles, potentially increasing the likelihood of restoring ovarian function following ovarian tissue autotransplantation. Clin Cancer Res; 22(22); 5506-13. ©2016 AACR.

Identification of cell-surface markers for detecting breast cancer cells in ovarian tissue.

PURPOSE: The safety of ovarian tissue autotransplantation in oncology patients cannot be ensured, as current tumor-detection methods compromise the ovarian tissue viability. Although non-destructive methods (for instance near-infrared fluorescence imaging) can discriminate malignant from healthy tissues while leaving the examined tissues unaffected, they require specific cell-surface tumor markers. We determined which tumor markers are suitable targets for tumor-specific imaging to exclude the presence of breast cancer cells in ovarian tissue. METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded specimens of ten ovaries from premenopausal patients. Additionally, we screened a tissue microarray containing tumor tissue cores from 24 breast cancer patients being eligible for ovarian tissue cryopreservation. The following cell-surface tumor markers were tested: E-cadherin, EMA (epithelial membrane antigen), Her2/neu (human epidermal growth factor receptor type 2), αvß6 integrin, EpCAM (epithelial cell adhesion molecule), CEA (carcinoembryonic antigen), FR-α (folate receptor-alpha), and uPAR (urokinase-type plasminogen activator receptor). For each tumor, the percentage of positive breast tumor cells was measured. RESULTS: None of the ten ovaries were positive for any of the markers tested. However, all markers (except CEA and uPAR) were present on epithelial cells of inclusion cysts. E-cadherin was present in the majority of breast tumors: ≥90 % of tumor cells were positive for E-cadherin in 17 out of 24 tumors, and 100 % of tumor cells were positive in 5 out of 24 tumors. CONCLUSIONS: Of the markers tested, E-cadherin is the most suitable marker for a tumor-specific probe in ovarian tissue. Methods are required to distinguish inclusion cysts from breast tumor cells.

Validation of a Dutch Version of the Reproductive Concerns Scale (RCS) in Three Populations of Women.

We investigated the psychometric properties of a Dutch version of the Reproductive Concerns Scale (RCS). Questionnaires (N = 515) were administered to 90 women with breast cancer, 227 women with fertility problems, and 198 healthy controls. Principal axis factor analysis suggested a one-factor structure with 11 items (breast cancer patients R(2) =.48, α =.87, ICC =.95; women with fertility problems R(2) =.45, α =.89, ICC =.86). Women with fertility problems reported the most concerns (M = 21.8, SD = 9.6), followed by breast cancer patients (M = 14.8, SD = 10.0) and healthy controls (M = 6.4, SD = 7.0). Theoretically related constructs were correlated to the RCS (.33 < r >.73). The RCS seems to be a valid tool for assessing women's reproductive concerns.

Searching for metastases in ovarian tissue before autotransplantation: a tailor-made approach.

OBJECTIVE: To exclude minimal residual disease in remaining ovarian tissue after harvesting the ovarian cortex for cryopreservation, by means of a tailor-made approach. DESIGN: Retrospective case series. SETTING: Hospital laboratory. PATIENT(S): We evaluated the ovarian and tubal tissue from 47 cancer patients (breast cancer, [non-]Hodgkin lymphoma; osteo-, Ewing, myxoid lipo-, and oropharyngeal synovial sarcoma; cervical, rectal, and esophageal cancer), who had stored ovarian tissue for fertility preservation. INTERVENTION(S): Immunohistochemistry (IHC) with tumor-related antibodies and genetic mutation analysis were performed to detect micrometastases by multiple sectioning at three levels of the paraffin-embedded formalin-fixed material. Molecular assays were performed with the use of tissue between these three levels of sectioning. MAIN OUTCOME MEASURE(S): Detection of micrometastases in ovaries. RESULT(S): We analyzed 847 ovarian slides to detect isolated tumor cells (ITCs) or micrometastases by IHC. In only one case (1/47) were ITCs detected in the fallopian tube. That patient had an intra-abdominal metastatic esophageal carcinoma. Additional DNA analyses of breast and rectal cancer, Ewing sarcoma, and human papilloma virus in cervical patients did not show evidence of micrometastases in the ovarian tissue. CONCLUSION(S): The tailor-made approach consisted of patient-specific tumor markers which were used to search for ovarian micrometastases. We found evidence of metastatic disease within the fallopian tube of a patient with intraperitoneal metastatic esophageal adenocarcinoma.

Women's experiences with information provision and deciding about fertility preservation in the Netherlands: 'satisfaction in general, but unmet needs'.

OBJECTIVE: It is not well-known how women receiving counselling consultation about fertility preservation (FP) in the Netherlands perceive the information provision about and referral for FP in the oncology setting. The aim of this study was to qualitatively explore women's experiences with the (process of) information provision about the gonadotoxic effects of cancer treatment and about FP and the decision-making process and to obtain their recommendation for improvements. METHODS: Semi-structured interviews with female patients with cancer who had received a counselling consultation on FP (at 18-40 years of age). RESULTS: Thirty-four interviews were held (response rate 64%). Information provision was considered to be important. Overall, women were satisfied with the timing and the content of the information, but women were less positive about the need to be assertive to get information, and the multiplicity of decisions and actions to be carried out in a very short time frame. CONCLUSIONS: Information provision on gonadotoxic effects of cancer treatment and about FP was overall deemed sufficient, timely and important. Women recommended standardization of the information provision, improvement of communication among clinicians and medical centres, and availability of FP-specific patient information materials to improve future information provision processes.

Development of a Decision Aid about fertility preservation for women with breast cancer in The Netherlands.

OBJECTIVES: To improve information provision about fertility preservation for breast cancer patients in the Netherlands, a web-based Decision Aid (DA) with additional values clarification exercise was developed according to the International Patient Decision Aid Standards criteria. This study reports on development of the DA. METHODS: Development consisted of four stages: (I) development of a draft DA, (II) acceptability of the draft DA to patients, (III) understanding (knowledge) in healthy populations, (IV) acceptability of the revised DA among patients and physicians. The study population consisted of 185 participants: 20 patients, 17 physicians and 148 healthy volunteers. RESULTS: The draft DA was considered to be relevant and understandable by patients, physicians and healthy volunteers. The values clarification exercise needed adaptation in explanation and navigation, which was done after stage II. Knowledge scores improved by 18% for lower educated women (from 4.1 (41%) to 5.9 (59%) correct answers), and by 34% for higher educated women after viewing the website (from 3.9 (39%) to 7.3 (73%) correct answers). Design of the DA was evaluated to be clear, but not always very appealing. CONCLUSIONS: The DA was regarded as a relevant source of information that seemed coherent and understandable.

Oncologists' practice and attitudes regarding fertility preservation in female cancer patients: a pilot study in the Netherlands.

PURPOSE: The aim of this study was to assess oncologists' practice and attitudes regarding treatment-related infertility and fertility preservation in female cancer patients of reproductive age. PARTICIPANTS AND METHODS: Recruitment letters with a 7-item questionnaire were sent to 454 oncologists. RESULTS: Two hundred and six of the 454 physicians (45%) responded and 96 questionnaires were used for analysis. The sample included 28 (29%) gynaecologists, 22 (23%) medical oncologists, 19 (20%) surgeons, 16 (17%) radiotherapists and 11 (12%) haematologists. Sixty-two percent of the physicians took action to protect ovarian function before or during gonadotoxic therapy. The most important reason for not offering fertility preservation was "factors concerning the disease". About one-third of the oncologists did not discuss fertility issues. Nearly half of the physicians (43%) would offer fertility preservation options, if they were standardized. High importance was given by almost all physicians (96%) to quality of life in general after gonadotoxic therapy and to the provision of information about fertility preservation options (81%). However, when asked about the importance of infertility after a malignancy, a smaller majority of the physicians (59%) gave it high importance. CONCLUSION: Most physicians considered infertility to be a major issue to be discussed, and most intended to take action to protect ovarian function before or during gonadotoxic therapy.

A Delphi consensus study among patients and clinicians in the Netherlands on the procedure of informing young breast cancer patients about Fertility Preservation.

BACKGROUND: The aim of this study was to obtain feedback from, and reach consensus among different experts who are or have been involved in information provision about FP, regarding the (procedure of) information provision about Fertility Preservation (FP) and use of a web-based decision aid (DA) about FP to create optimal conditions for the implementation of the DA-website, as we prepare to implement a DA about FP in the Netherlands. MATERIAL AND METHODS: A two round Delphi study in which experts (patients and clinicians) rated their (dis)agreement with a list of statements (Rounds 1, 2), and additional online forum to discuss dissensus (Round 3). We assessed opinions about FP, web-based DAs, and about the procedure of informing patients. Answer categories ranged from 1 (totally disagree) to 5 (totally agree). Consensus was considered significant when at least 80% of the experts scored either the lowest or the highest two categories. RESULTS: Experts reached rapid consensus on all five statements about the use of a DA (5/5; 100%), and all eight statements about which patients should be offered information about FP (8/8; 100%). However opinions about FP (4/11 statements; 36%), and procedural aspects such as who should inform the patient (6/10 statements; 60%) and when (3/10 statements; 30%) remained for discussion in round 3. In the online discussion some level of agreement was reached for these statements after all. CONCLUSION: It was deemed important that FP options exist. Every eligible patient should receive at least some (general) information about FP, soon after diagnosis. Detailed information should be provided by a fertility expert at a later moment. Exact timing and amount of information should be adjusted to patient's needs and situational context. A DA-website can offer a fair contribution to this.