Impact of timing and format of patient decision aids for breast cancer patients on their involvement in and preparedness for decision making - the IMPACTT randomised controlled trial protocol.

BACKGROUND: After curative surgery for early-stage breast cancer, patients face a decision on whether to undergo surgery alone or to receive one or more adjuvant treatments, which may lower the risk of recurrence. Variations in survival outcomes are often marginal but there are differences in the side effects and other features of the options that patients may value differently. Hence, the patient's values and preferences are critical in determining what option to choose. It is well-researched that the use of shared decision making and patient decision aids can support this choice in a discussion between patient and clinician. However, it is still to be investigated what impact the timing and format of the patient decision aid have on shared decision making outcomes. In this trial, we aim to investigate the impact of a digital pre-consult compared to a paper-based in-consult patient decision aid on patients' involvement in shared decision making, decisional conflict and preparedness to make a decision. METHODS: The study is a randomised controlled trial with 204 patients at two Danish oncology outpatient clinics. Eligible patients are newly diagnosed with early-stage breast cancer and offered adjuvant treatments after curative surgery to lower the risk of recurrence. Participants will be randomised to receive either an in-consult paper-based patient decision aid or a pre-consult digital patient decision aid. Data collection includes patient and clinician-reported outcomes as well as observer-reported shared decision making based on audio recordings of the consultation. The primary outcome is the extent to which patients are engaged in a shared decision making process reported by the patient. Secondary aims include the length of consultation, preparation for decision making, preferred role in shared decision making and decisional conflict. DISCUSSION: This study is the first known randomised, controlled trial comparing a digital, pre-consult patient decision aid to an identical paper-based, in-consult patient decision aid. It will contribute evidence on the impact of patient decision aids in terms of investigating if pre-consult digital patient decisions aids compared to in-consult paper-based decision aids support the cancer patients in being better prepared for decision making. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05573022).

Decision aids for people facing health treatment or screening decisions.

BACKGROUND: Patient decision aids are interventions designed to support people making health decisions. At a minimum, patient decision aids make the decision explicit, provide evidence-based information about the options and associated benefits/harms, and help clarify personal values for features of options. This is an update of a Cochrane review that was first published in 2003 and last updated in 2017. OBJECTIVES: To assess the effects of patient decision aids in adults considering treatment or screening decisions using an integrated knowledge translation approach. SEARCH METHODS: We conducted the updated search for the period of 2015 (last search date) to March 2022 in CENTRAL, MEDLINE, Embase, PsycINFO, EBSCO, and grey literature. The cumulative search covers database origins to March 2022. SELECTION CRITERIA: We included published randomized controlled trials comparing patient decision aids to usual care. Usual care was defined as general information, risk assessment, clinical practice guideline summaries for health consumers, placebo intervention (e.g. information on another topic), or no intervention. DATA COLLECTION AND ANALYSIS: Two authors independently screened citations for inclusion, extracted intervention and outcome data, and assessed risk of bias using the Cochrane risk of bias tool. Primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were attributes related to the choice made (informed values-based choice congruence) and the decision-making process, such as knowledge, accurate risk perceptions, feeling informed, clear values, participation in decision-making, and adverse events. Secondary outcomes were choice, confidence in decision-making, adherence to the chosen option, preference-linked health outcomes, and impact on the healthcare system (e.g. consultation length). We pooled results using mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs), applying a random-effects model. We conducted a subgroup analysis of 105 studies that were included in the previous review version compared to those published since that update (n = 104 studies). We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess the certainty of the evidence. MAIN RESULTS: This update added 104 new studies for a total of 209 studies involving 107,698 participants. The patient decision aids focused on 71 different decisions. The most common decisions were about cardiovascular treatments (n = 22 studies), cancer screening (n = 17 studies colorectal, 15 prostate, 12 breast), cancer treatments (e.g. 15 breast, 11 prostate), mental health treatments (n = 10 studies), and joint replacement surgery (n = 9 studies). When assessing risk of bias in the included studies, we rated two items as mostly unclear (selective reporting: 100 studies; blinding of participants/personnel: 161 studies), due to inadequate reporting. Of the 209 included studies, 34 had at least one item rated as high risk of bias. There was moderate-certainty evidence that patient decision aids probably increase the congruence between informed values and care choices compared to usual care (RR 1.75, 95% CI 1.44 to 2.13; 21 studies, 9377 participants). Regarding attributes related to the decision-making process and compared to usual care, there was high-certainty evidence that patient decision aids result in improved participants' knowledge (MD 11.90/100, 95% CI 10.60 to 13.19; 107 studies, 25,492 participants), accuracy of risk perceptions (RR 1.94, 95% CI 1.61 to 2.34; 25 studies, 7796 participants), and decreased decisional conflict related to feeling uninformed (MD -10.02, 95% CI -12.31 to -7.74; 58 studies, 12,104 participants), indecision about personal values (MD -7.86, 95% CI -9.69 to -6.02; 55 studies, 11,880 participants), and proportion of people who were passive in decision-making (clinician-controlled) (RR 0.72, 95% CI 0.59 to 0.88; 21 studies, 4348 participants). For adverse outcomes, there was high-certainty evidence that there was no difference in decision regret between the patient decision aid and usual care groups (MD -1.23, 95% CI -3.05 to 0.59; 22 studies, 3707 participants). Of note, there was no difference in the length of consultation when patient decision aids were used in preparation for the consultation (MD -2.97 minutes, 95% CI -7.84 to 1.90; 5 studies, 420 participants). When patient decision aids were used during the consultation with the clinician, the length of consultation was 1.5 minutes longer (MD 1.50 minutes, 95% CI 0.79 to 2.20; 8 studies, 2702 participants). We found the same direction of effect when we compared results for patient decision aid studies reported in the previous update compared to studies conducted since 2015. AUTHORS' CONCLUSIONS: Compared to usual care, across a wide variety of decisions, patient decision aids probably helped more adults reach informed values-congruent choices. They led to large increases in knowledge, accurate risk perceptions, and an active role in decision-making. Our updated review also found that patient decision aids increased patients' feeling informed and clear about their personal values. There was no difference in decision regret between people using decision aids versus those receiving usual care. Further studies are needed to assess the impact of patient decision aids on adherence and downstream effects on cost and resource use.

Communicating without a Shared Language: A Qualitative Study of Language Barriers in Language-Discordant Cancer Communication.

We use language to achieve understanding, and language barriers can have major health consequences for patients with serious illness. While ethnic minorities are more likely to experience social inequalities in health and health care, communicative processes in language-discordant cancer care remain unexplored. This study aimed to investigate communication between patients with cancer and limited Danish proficiency and oncology clinicians, with special emphasis on how linguistic barriers influenced patient involvement and decision-making. 18 participant observations of clinical encounters were conducted. Field notes and transcriptions of audio recordings were analyzed, and three themes were identified: Miscommunication and uncertainty as a basic linguistic condition; Impact of time on patient involvement; Unequally divided roles and (mis)communication responsibilities. The results showed that professional interpreting could not eradicate miscommunication but was crucial for achieving understanding. Organizational factors related to time and professional interpreting limited patient involvement. Without professional interpreting, patients' relatives were assigned massive communication responsibilities. When no Danish-speaking relatives partook, clinicians' ethical dilemmas further increased as did patient safety risks. Language barriers have consequences for everyone who engages in health communication, and the generated knowledge about how linguistic inequality manifests itself in clinical practice can be used to reduce social inequalities in health and health care.

Prognostic impact of early ctDNA dynamics during chemotherapy of metastatic cancer.

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41-0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy.

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer.

BACKGROUND: Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. METHODS: Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. RESULTS: CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)-CD47 (cancer cells), MDK (CAFs)-NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. CONCLUSIONS: This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer. Video abstract.

Impact of veliparib, paclitaxel dosing regimen, and germline BRCA status on the primary treatment of serous ovarian cancer - an ancillary data analysis of the VELIA trial.

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status. METHODS: Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status. RESULTS: 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups. CONCLUSIONS: DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

Impact of homologous recombination status and responses with veliparib combined with first-line chemotherapy in ovarian cancer in the Phase 3 VELIA/GOG-3005 study.

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. METHODS: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. RESULTS: Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. CONCLUSIONS: These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.

When life gives you no choice: Context of decision-making when offered an oncology clinical trial.

BACKGROUND: Patients with advanced cancer are faced with a wide variety of challenges and difficult treatment decisions made while in a vulnerable life-threatening situation, including decisions about clinical trial participation. Internationally, there is a great focus on shared decision-making as a way to help patients and healthcare professionals to make informed decisions together; nevertheless, research focusing on patient experiences shows that information about clinical trials is insufficient in supporting patients to make trial decisions in the context of their course of disease and managing life with advanced cancer. AIM: To explore where and how decisions about participation in oncology clinical trials are made and the role of the patients and healthcare professionals. METHODS: Participant observation was used as a qualitative research method to gain knowledge about decision-making in different clinical situations. Data were analysed using thematic analysis. RESULTS: Four themes were developed: (a) preformed decisions, (b) dissimilar perceptions of successful treatment, (c) cues and concerns stated by patients and (d) creating common ground. CONCLUSION: There are underexposed aspects to be aware of in the decision-making process for clinical trial participation. Preformed decisions made by the physicians before the encounter with patients seemed to narrow down the patients' options and could have benefited from including the patients' views. Cues and concerns stated by patients were often neglected. However, when physicians talked with the patients about truly difficult issues such as treatment expectations, hope and death, it led to another kind of conversation about treatment decisions involving the patients' preferences. IMPLICATIONS FOR PRACTICE: Awareness of preformed decisions and an increased focus on picking up cues and concerns about existential issues in the clinical encounter may improve the quality of the decisions and increase shared decision-making.

Patients' experiences of the decision-making process for clinical trial participation.

Clinical decision-making about participating in a clinical trial is a complex process influenced by overwhelming information about prognosis, disease, and treatment options. The study aimed to explore patients' experiences of the decision-making process when patients are presented with the opportunity to participate in a cancer clinical trial and to shed light on how patients experience the health communication, the nurse's role, and the physician's role. A qualitative study design was applied. Nine patients with advanced cancer were interviewed after being informed about their treatment options. Data were analyzed using thematic analysis. The results showed that patients made treatment decisions mainly guided by their emotions and trust in the physician. Furthermore, the physicians had a great impact on the decisions, and the nurse's role was associated with conversations about how to manage life. The study highlights the importance of talking about prognosis and addressing the patient's existential issues, particularly in this context of advanced cancer. The study elucidates a need for healthcare professionals to engage in health communication about life when it is coming to an end.

Progression-free survival by investigator versus blinded independent central review in newly diagnosed patients with high-grade serous ovarian cancer: Analysis of the VELIA/GOG-3005 trial.

OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR). METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRD + BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed. RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5 months in the veliparib-throughout arm versus 17.3 months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; P < 0.001). Median PFS by BICR was 29.3 months versus 19.2 months (HR 0.687, 95% CI 0.504-0.806). In the ITT population, the overall concordance rates between INV and BICR were 78% and 75% for the veliparib-throughout and control arms, respectively. CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.

The PROMova study comparing active and passive use of patient-reported outcome measures in ovarian cancer follow-up: effect on patient-perceived involvement, satisfaction with care, and usefulness.

BACKGROUND: Patients with ovarian cancer often experience substantial health problems and side effects resulting in reduced quality of life (QoL). Different models of using patient-reported outcome measures (PROMs) during follow-up may improve the quality of care. This national, multicenter observational study investigated the effect of active use of PROMs on patient-perceived involvement, satisfaction with care, unmet needs, and QoL during follow-up of ovarian cancer. MATERIAL AND METHODS: Ovarian cancer patients were recruited at the end of primary treatment at eight centers in Denmark. During 18 months of follow-up patients repeatedly completed European Organization for Research and Treatment of Cancer (EORTC) questionnaires covering health related QoL and symptoms. At the sites using PROMs actively (ACT), the clinician had access to an overview of the patient's scores during the clinical encounter. Clinicians using PROMs passively were alerted in case of severe development of symptoms. Following each encounter, patients evaluated their health service experience by completing the CollaboRATE scale of involvement in decision making, the Patient Experience Questionnaire, and ad hoc questions covering patient-perceived usefulness of the PROMs. RESULTS: A total of 223 patients were enrolled, i.e., 168 (75.3%) at five sites using ACT and 53 (23.8%) at three sites using them passively. We found no statistically significant difference in involvement in the decision making, satisfaction with care, unmet needs, and QoL between the two groups. The majority of patients found it useful to complete the PROMs, although it did not seem to significantly support them in raising issues with the oncologist. CONCLUSION: Active use of PROMs did not improve patients' experience of involvement in follow-up care as compared to passive use.

Treosulfan in platinum-resistant ovarian cancer.

OBJECTIVES: Treosulfan is offered as last-line treatment in patients with end-stage ovarian cancer. This retrospective study aimed to evaluate the response rates, overall survival, and adverse events of treosulfan in this patient population. METHODS: The study included patients with end-stage platinum-resistant ovarian cancer treated with treosulfan from October 2015 to October 2020 at the Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark. Patients were included for treatment if their cancer had progressed and if other treatment options were limited. Patients receiving treosulfan as first-line treatment were excluded from the study. Response rates were evaluated according to the combined criteria of CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Kaplan-Meier survival analyses were used to illustrate progression-free and overall survival. Adverse events were graded 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Sixty-seven patients with a median age of 72 years (range 33-92) were identified. Sixty-three (94%) patients were diagnosed with serous adenocarcinoma. Fifty-seven (85%) patients were Federation of International Gynecology and Obstetrics (FIGO) stage III or IV at the time of diagnosis. The median number of treatments prior to treosulfan treatment was 3 (range 1-8). One patient had a complete response (2%), eight patients had a partial response (13%), and 22 patients (35%) had stable disease as the best response. The median duration of response (complete or partial) was 239 days (range 43-572). Median progression-free survival was 63 days (95% CI 41 to 77). The most common adverse events were anemia (83%), fatigue (83%), anorexia (62%), nausea (57%), and constipation (41%). CONCLUSIONS: Treosulfan is an alternative for the treatment of relapsed ovarian cancer when other treatment options are limited, with response rates of approximately 15%. In general, the treatment was well tolerated. Taking the mild adverse events and the response rates into account, palliative treosulfan mainly seems beneficial for patients with performance status 0-1.

Association of patient-reported outcomes and ovarian cancer recurrence.

BACKGROUND: The vast majority of patients with advanced ovarian cancer experience disease recurrence after primary treatment. OBJECTIVE: To explore the diagnostic accuracy of repeated measurement of patient-reported outcomes and quality-of-life scores in relation to ovarian cancer recurrence. METHODS: Patients with ovarian cancer were recruited to the PROMova study by the end of their primary treatment at eight centers in Denmark. The purpose of the PROMova study was to explore the applicability of repeated use of patient-reported outcomes, which consisted of the European Organization for Research and Treatment of Cancer generic questionnaire and the ovarian specific questionnaire. The patient-reported outcomes were completed 3, 6, 9, 12, and 15 months after enrollment or until recurrence. The 3-month interval between completions was the period in which recurrence was assessed. Imaging and the biomarker CA125 were used as reference modality for recurrence. Mixed effects logistic regression was used to investigate the association between mean patient-reported outcome scores and recurrence. Receiver operating curves were used to establish cut-off scores. The diagnostic accuracy of patient-reported outcomes, including sensitivity, specificity, and positive and negative predictive values was estimated based on the Youden index. For combined scales, diagnostic accuracy was investigated based on multivariate analysis. RESULTS: The analysis included 196 patients with an overall recurrence rate of 50.5% and an overall mean time to recurrence of 302 days. With imaging as reference, patients with recurrence reported significantly lower global health, worse physical functioning, and more abdominal symptoms preceding recurrence. With CA125 as reference, global health, physical and emotional functioning were impaired. Despite the worsening of a number of symptoms prior to recurrence whichever reference modality was applied, the patient-reported outcome scores did not provide adequate diagnostic accuracy. CONCLUSION: Repeated use of patient-reported outcomes during surveillance of ovarian cancer was not of diagnostic value. Future efforts should be directed at improving the administration of patient-reported outcomes as well as exploring the potential of using these outcomes as an indicator of clinical relevance.

Blood natural killer cells during treatment in recurrent ovarian cancer.

OBJECTIVE: Recent research indicated favorable prognostic impact of intratumoral natural killer (NK) cells in ovarian carcinoma (OC). The role of NK cells during chemotherapy in OC is unknown. We investigated impact of NK cells in OC patients treated with palliative chemotherapy. METHODS: Participants receiving palliative chemotherapy for recurrent OC (N = 72) had prospectively blood samples at baseline and before cycle 2. NK cell counts were quantified by flow cytometry. NK cell activity was measured by the NK Vue® assay, estimating interferon-gamma production. Overall survival (OS) was the primary endpoint. Cutoffs were predefined, NK numbers (≥184 × 106 cells/L vs. <184 × 106 cells/L) and NK activity (<200 pg/mL vs. ≥200 pg/mL). RESULTS: Median OS in patients with low vs. high NK cell count at baseline was 7.1 months vs. 15.6 months (p = .028), respectively, and before cycle 2 was 5.7 vs. 17.3 months, p < .001, respectively. The difference in restricted mean survival (ΔRMST) was 5.7 months (95% CI: 3.3-8.0) at cycle 2 vs. 2.5 months (95% CI: -0.6 to 5.6) at baseline, showing a significant difference with no overlap of confidence intervals. In multivariate analyses, low NK cell count remained significant with a hazard ratio (HR)=2.83, 95% CI: 1.53-5.22, p = .001 (baseline) and HR = 3.34, 95% CI: 1.67-6.71, p = .001 (before cycle 2). Patients with both low NK count and NK activity at baseline (N = 20) had median OS 6.5 months vs. 11.5 months in patients with either high activity, high count or both (p = .007). In parallel, patients with both low NK activity and count at cycle 2 (N = 18) had a median survival of 4.0 months vs. 15.4 months (p < .001). CONCLUSIONS: A low blood NK cell count in recurrent metastatic ovarian cancer during chemotherapy is associated with unfavorable prognostic impact. Early increase in survival difference based on NK cell status suggests an association between NK cell count and treatment benefit.

Satisfaction with care and adherence to treatment when using patient reported outcomes to individualize follow-up care for women with early breast cancer - a pilot randomized controlled trial.

Background: The population of breast cancer survivors is increasing as a positive consequence of early detection and enhanced treatment. The disease and treatment associated side-effects or late-effects often impact on quality of life and daily life functions during survivorship. This calls for optimization of follow-up care. We aimed to evaluate the patients' satisfaction with the care provided, when using electronic patient reported outcomes (ePROs) to individualize follow-up care in women with early breast cancer receiving adjuvant endocrine therapy.Material and methods: Postmenopausal women treated for hormone receptor positive early breast cancer were included in a pilot randomized controlled trial and randomized to receive standard follow-up care with prescheduled consultations every six months or individualized follow-up care with the active use of ePROs to screen for the need of consultations. ePROs were distributed every third month over a two-year period. Primary outcomes were satisfaction with the assigned follow-up care and unmet needs. Secondary outcomes were use of consultations, adherence to treatment and quality of life.Results: Of the 207 consecutive patients who were potentially eligible for the study, 134 women were enrolled (65%). In total 64 women in standard care and 60 women in individualized care were analyzed. No statistically significant differences were reported in relation to satisfaction, unmet needs, adherence to treatment or quality of life. Women in standard care attended twice as many consultations during the two year follow-up period as women in individualized care; 4.3 (95% CI 3.9-4.7) versus 2.1 (95% CI: 1.6-2.6), p < .001.Conclusion: A significant reduction in consultations was observed for the group attending individualized care without compromising the patients' satisfaction, quality of life or adherence to treatment. For the majority of postmenopausal women treated for early breast cancer, implementation of ePROs to individualize follow-up care was feasible.

Favorable prognostic impact of Natural Killer cells and T cells in high-grade serous ovarian carcinoma.

Introduction: The aim of the present study was to investigate the prognostic impact of intratumoral cytotoxic T cells, Natural Killer (NK) cells, neutrophils and PD-L1 expression in patients with epithelial ovarian cancer.Methods: All patients diagnosed with high-grade serous carcinoma (HGSC) in Denmark in 2005 were included in the study. Immunohistochemical staining for PD-L1, CD8, CD66b and CD57 was performed on tumor tissue from 283 patients. Cell densities were analyzed using a digital image analysis method. The primary endpoint was overall survival (OS).Results: The median OS for HGSC patients was 30 months. It was 45 months in patients with high level of CD57+ NK cells (≥10 cells/mm2) compared with 29 month in patients with low level (<10 cells/mm2) (p = .0310). The median OS was 37 and 25 months in patients with high vs. low level of CD8+ T cells (cutoff 80 cells/mm2) (p = .0008). In multivariate analysis, high numbers of CD57+ NK cells and CD8+ T cells remained independent markers of favorable OS, adjusted hazard ratio (HR) 0.67; p = .041, and HR 0.72; p = .020, respectively. PD-L1 expression was associated with improved OS (37 months vs. 22 months, p = .0006), but was only borderline significant in the multivariate analysis (HR 0.77, p = .061). CD66b + neutrophils had no association with OS.Conclusions: In patients with HGSC tumor-infiltrating CD57+ NK cells and CD8+ T cells had favorable prognostic impact, while PD-L1 expression had borderline favorable prognostic significance. CD66b + neutrophils had no prognostic association. These findings may influence future immunotherapy development.

Use of PROM during follow-up of patients with ovarian cancer: the PROMova study protocol.

BACKGROUND: There is a paucity of high-level evidence on the optimal follow-up of patients with ovarian cancer after primary treatment. A debate is ongoing on the extent to which follow-up should consider patient preferences and patient-reported outcome measures. Incorporation of patient-reported outcome measures supports the dialog between patient and clinician and may be instrumental in symptom monitoring and detection of underlying issues, especially when used actively during the clinical consultation. PRIMARY OBJECTIVE AND ENDPOINT: The PROMova study aims to assess whether proactive use of patient-reported outcome measures during follow-up care increases patient involvement as perceived by the patient compared with standard care. Another objective is to measure satisfaction with the care provided. STUDY HYPOTHESIS: It is hypothesized that proactive use of patient-reported outcome measures during the clinical encounter will improve patients' experience of involvement in follow-up care. TRIAL DESIGN: PROMova is a multi-center, observational cohort study collecting data from eight departments in Denmark. Five departments use the patient-reported outcome measures proactively during the consultation and three provide standard care. Participants are followed up with patient-reported outcome measures for up to 3 years. The patient-reported outcome measures package comprises EORTC QLQ-C30, EORTC QLQ-OV28, a questionnaire screening tool for recurrence, CollaboRATE, and selected questions from the Patient Experience Questionnaire. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients older than 18 years diagnosed with ovarian, fallopian tube, or primary peritoneal cancer are eligible when entering the follow-up program after primary treatment. Participants must be able to speak and read Danish. SAMPLE SIZE: 223 patients with ovarian cancer. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The protocol closed for enrollment in 2019. Publication of final results is expected in spring 2022. TRIAL REGISTRATION: PROMova was registered with ClinicalTrials.gov November 2016 Identifier: NCT02916875.

Delta tocotrienol in recurrent ovarian cancer. A phase II trial.

Delta tocotrienol has anti-neoplastic activity as demonstrated in several in-vitro and in-vivo investigations. The effect relies on inhibition of different pathways. It also has antiangiogenic activity, and an additive effect to bevacizumab may be expected. The present study was a phase II trial of bevacizumab combined with tocotrienol in chemotherapy refractory ovarian cancer. The study also included analysis of circulating tumor specific HOXA9 methylated DNA (HOXA9 meth-ctDNA) during treatment. The study included 23 patients. The rate of disease stabilization was 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high compared to the current literature. A division of the patients according to level of HOXA9 meth-ctDNA already after the first cycle of chemotherapy resulted in two groups of patients with different prognoses. Patients with an increasing level of HOXA9 meth-ctDNA had a median PFS and OS of 1.4 and 4.3 months, respectively, compared to 7.8 and 12 months in the group with stable or decreasing levels. The combination of bevacizumab and tocotrienol is potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy holds important prognostic information.

The clinical importance of BRCAness in a population-based cohort of Danish epithelial ovarian cancer.

OBJECTIVE: Germline mutations in BRCA1/2 genes predict improved survival and sensitivity to treatment with poly(adenosine-diphosphate-ribose) polymerase inhibitors in epithelial ovarian carcinoma. The prognostic importance of other genetic alterations leading to homologous recombination deficiency, collectively BRCAness phenotype, is unresolved. The aim was to analyze the distribution of homologous recombination deficiency in epithelial ovarian carcinoma caused by mutations in a panel of homologous recombination genes (including BRCA1/2) or epigenetic alterations. A further aim was to investigate the prognostic importance of homologous recombination deficiency, the BRCAness phenotype. METHODS: We assessed 380 patient specimens from a Danish population-based epithelial ovarian carcinoma cohort for germline and somatic mutations in 18 different homologous recombination genes, including BRCA1 and BRCA2, using next generation sequencing. Epigenetic alteration due to BRCA1 hypermethylation was assessed by pyrosequencing and BRCA1 protein expression was evaluated by immunohistochemistry. RESULTS: Seventeen percent of patients with epithelial ovarian carcinoma carried a germline (9.8%) and/or somatic (6.3%) mutation in 12 (BRCA1, BRCA2, CHEK2, ATM, RAD51D, EMSY, PALB2, BRIP1, ERCC1, RAD50, ATR, RAD51C) of 18 sequenced homologous recombination genes. The homologous recombination mutation rate was similar among the different histologic subtypes, however the type of mutation (BRCA1/2 and other homologous recombination mutations) differed, p=4×10-4. BRCA1 hypermethylation was present in 7.4% of patient specimens for a total BRCAness phenotype of 23.9%. The BRCAness phenotype was associated with improved overall survival in the high-grade serous carcinoma subgroup with a median overall survival of 4.4 years (95% CI 3.0 to 5.3) versus 2.2 years (95% CI 1.9 to 2.4) in BRCAness wildtype, p=0.0002. Multivariate analysis confirmed an independent prognostic value of the BRCAness phenotype among the high-grade serous carcinoma subgroup, hazard ratio 0.65 (95% CI 0.47 to 0.92), p=0.014. CONCLUSIONS: The BRCAness phenotype is present in almost one-fourth of epithelial ovarian carcinoma and holds important prognostic information. The implications of our findings in relation to poly(adenosine-diphosphate-ribose) polymerase inhibitor treatment call for further investigation.