An eHealth App (CAPABLE) Providing Symptom Monitoring, Well-Being Interventions, and Educational Material for Patients With Melanoma Treated With Immune Checkpoint Inhibitors: Protocol for an Exploratory Intervention Trial.

BACKGROUND: Since treatment with immune checkpoint inhibitors (ICIs) is becoming standard therapy for patients with high-risk and advanced melanoma, an increasing number of patients experience treatment-related adverse events such as fatigue. Until now, studies have demonstrated the benefits of using eHealth tools to provide either symptom monitoring or interventions to reduce treatment-related symptoms such as fatigue. However, an eHealth tool that facilitates the combination of both symptom monitoring and symptom management in patients with melanoma treated with ICIs is still needed. OBJECTIVE: In this pilot study, we will explore the use of the CAPABLE (Cancer Patients Better Life Experience) app in providing symptom monitoring, education, and well-being interventions on health-related quality of life (HRQoL) outcomes such as fatigue and physical functioning, as well as patients' acceptance and usability of using CAPABLE. METHODS: This prospective, exploratory pilot study will examine changes in fatigue over time in 36 patients with stage III or IV melanoma during treatment with ICI using CAPABLE (a smartphone app and multisensory smartwatch). This cohort will be compared to a prospectively collected cohort of patients with melanoma treated with standard ICI therapy. CAPABLE will be used for a minimum of 3 and a maximum of 6 months. The primary endpoint in this study is the change in fatigue between baseline and 3 and 6 months after the start of treatment. Secondary end points include HRQoL outcomes, usability, and feasibility parameters. RESULTS: Study inclusion started in April 2023 and is currently ongoing. CONCLUSIONS: This pilot study will explore the effect, usability, and feasibility of CAPABLE in patients with melanoma during treatment with ICI. Adding the CAPABLE system to active treatment is hypothesized to decrease fatigue in patients with high-risk and advanced melanoma during treatment with ICIs compared to a control group receiving standard care. The Medical Ethics Committee NedMec (Amsterdam, The Netherlands) granted ethical approval for this study (reference number 22-981/NL81970.000.22). TRIAL REGISTRATION: ClinicalTrials.gov NCT05827289; https://clinicaltrials.gov/study/NCT05827289. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49252.

Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma: A systematic scoping review.

INTRODUCTION: This systematic scoping review compares the toxicities experienced by patients receiving immune checkpoint inhibitors (ICIs) or targeted therapy (TT) for stage III (resected and unresectable) and stage IV melanoma. METHODS: OVID Medline, Embase, and PsycInfo were searched to identify Phase III trials reporting toxicities of FDA-approved ICIs and TT for advanced melanoma. AEs that were reported by ≥ 10% of patients in the evaluated trials were included. RESULTS: Toxicity profiles of 11208 patients from 24 studies were reviewed. The rate of AEs was lower with ICIs compared to TT. However, ICIs were associated with higher rates of long-term or permanent AEs compared to TT, where toxicities generally were shortterm and reversible with treatment discontinuation. CONCLUSION: The toxicity profiles of ICIs and TT vary substantially. Whilst the rate of AEs was lower with ICIs than during TT, it was also associated with higher rates of potentially chronic AEs.

Quality of early prostate cancer follow-up care from the patients' perspective.

PURPOSE: To develop optimal cancer survivorship care programs, this study assessed the quality of prostate cancer follow-up care as experienced by patients shortly after completion of primary treatment. METHODS: We surveyed 402 patients with localized prostate cancer participating in a randomized controlled trial comparing specialist versus primary care-based follow-up. For the current study, we used patient-reported data at the time of the first follow-up visit at the hospital, prior to randomization. We assessed patients' ratings of the quality of follow-up care using the Assessment of Patient Experiences of Cancer Care survey. This survey includes 13 scales about different aspects of care and an overall rating of care. Multivariable linear regression analysis was used to identify factors associated with perceived follow-up quality. RESULTS: Patients reported positive experiences at first follow-up for 9 of 13 scales, with mean (M) scores ranging from 79 to 97 (on a 0-100 response scale). Patients reported most frequently (over 70%) suboptimal care regarding symptom management (84%; M = 44, SD = 37), health promotion (75%; M = 45, SD = 39), and physician's knowledge about patients' life (84%; M = 65, SD = 23). Overall, patients' lower quality of follow-up ratings were associated with younger age, higher education level, having more than one comorbid condition, having undergone primary surgery, and experiencing significant symptoms. CONCLUSION: Patients with prostate cancer are generally positive about their initial, hospital-based follow-up care. However, efforts should be made to improve symptom management, health promotion, and physician's knowledge about patients' life. These findings point to areas where prostate cancer follow-up care can be improved.

Specialist versus Primary Care Prostate Cancer Follow-Up: A Process Evaluation of a Randomized Controlled Trial.

Background: A randomized controlled trial (RCT) is currently comparing the effectiveness of specialist- versus primary care-based prostate cancer follow-up. This process evaluation assesses the reach and identified constructs for the implementation of primary care-based follow-up. Methods: A mixed-methods approach is used to assess the reach and the implementation through the Consolidated Framework for Implementation Research. We use quantitative data to evaluate the reach of the RCT and qualitative data (interviews) to indicate the perspectives of patients (n = 15), general practitioners (GPs) (n = 10), and specialists (n = 8). Thematic analysis is used to analyze the interview transcripts. Results: In total, we reached 402 (67%) patients from 12 hospitals and randomized them to specialist- (n = 201) or to primary care-based (n = 201) follow-up. From the interviews, we identify several advantages of primary care- versus specialist-based follow-up: it is closer to home, more accessible, and the relationship is more personal. Nevertheless, participants also identified challenges: guidelines should be implemented, communication and collaboration between primary and secondary care should be improved, quality indicators should be collected, and GPs should be compensated. Conclusion: Within an RCT context, 402 (67%) patients and their GPs were willing to receive/provide primary care-based follow-up. If the RCT shows that primary care is equally as effective as specialist-based follow-up, the challenges identified in this study need to be addressed to enable a smooth transition of prostate cancer follow-up to primary care.

Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial.

Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg-1 and nivolumab 3 mg kg-1. In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab.

Exploring supportive care and information needs through a proposed eHealth application among melanoma patients undergoing systemic therapy: a qualitative study.

BACKGROUND: During and after systemic therapy, patients with high risk and advanced melanoma experience challenges regarding cancer-related symptoms, treatment-related adverse events, and an impact of these symptoms on their physical and psychosocial well-being. Few studies have investigated the specific needs of these patients and the potential role of eHealth applications in meeting those needs. OBJECTIVE: To explore the supportive care and information needs of high risk and advanced melanoma patients, and how these needs can be supported by eHealth applications. METHODS: In this qualitative study, semi-structured interviews with high risk and advanced melanoma patients during or after systemic treatment were conducted to understand their needs and requirements as possible end-users of mobile eHealth applications. Interview transcripts were independently coded and thematically analyzed. RESULTS: Thirteen participants consented to be interviewed, aged 31 to 71 years. Nearly all patients (n = 12, 92%) experienced unmet information and supportive care needs during and after active treatment. Patients expected to value eHealth applications that facilitate information gathering, wellbeing interventions, and symptom management. The majority of patients (n = 10, 77%) anticipated various advantages from using an eHealth application, including increased autonomy, higher quality of life, and improved disease self-management. DISCUSSION: High risk and advanced melanoma patients have unmet supportive care and information needs during and after systemic treatment. The use of eHealth applications might be an effective way to meet these unmet needs. Patients anticipate a variety of advantages from using these applications, including deriving various benefits from the use of these applications, such as enhanced autonomy.

Individual risk prediction of urinary incontinence after prostatectomy and impact on treatment choice in patients with localized prostate cancer.

AIMS: Individualized information about the risk of incontinence after prostatectomy could help patients in shared decision-making. METHODS: We compared a historical control cohort (n = 254; between June 2016 and 2017) that received standardized information about the risk of incontinence after robot-assisted radical prostatectomy (RARP) with a prospective patient cohort (n = 254; between June 2017 and May 2018) that received individualized information of the chance of recovery of incontinence within 6 months postoperatively based on the continence prediction tool (CPRED). We measured switch in treatment choice, health-related quality of life (QoL) in both cohorts and the accuracy of the CPRED tool. RESULTS: Patients in the individualized information group with RARP as initial preference switched more often to another treatment than patients who received standardized information (16% vs. 5%; p = 0.001). Patients in the individualized information group with a high risk of incontinence and with RARP as initial preference switched more often to other treatments than patients in intermediate/low risk of incontinence (35% vs. 9.8%; p = 0.001). Patients with a low risk of incontinence choosing RARP after individualized information were less likely to use more than one diaper a day at any time postoperative (p = 0.001) compared to men with an intermediate/high incontinence risk. Overall QoL was worse in patients with incontinence than patients with continence 6 and 12 months after RARP (respectively; p < 0.0001 and p = 0.007). CONCLUSION: Personalized information about the risk of incontinence after RARP makes more patients reconsidering their initial treatment preference. The CPRED correlated strongly with continence outcome after RARP and is a useful tool for shared decision-making.

A questionable factor structure of the multidimensional fatigue inventory in the general Dutch population.

OBJECTIVE: One of the most commonly used tools to measure fatigue is the Multidimensional Fatigue Inventory (MFI). Studies into the scale structure of the MFI show discrepant findings. The objective of this study was to investigate the scale structure of the MFI in the general Dutch population. STUDY DESIGN AND SETTING: Using data from a Dutch probability-based internet panel (n = 2512), the original 5-factor model, a 4-factor, and a 5- and 4-bifactor model of the MFI were tested with confirmatory factor analyses. Additional models were investigated using exploratory factor analysis. RESULTS: Results neither confirmed a 5-factor (RMSEA = 0.120, CFI = 0.933, TLI = 0.920) nor a 4-factor model (RMSEA = 0.122, CFI = 0.928, TLI = 0.917). The two bi-factor models also showed a poor fit (bi-4-factor: RMSEA = 0.151, CFI = 0.895, TLI = 0.873; bi-5-factor: RMSEA = 0.153, CFI = 0.894, TLI = 0.871). Exploratory factor analysis did not support an alternative model, but seemed to show robustness in the loading of the original general fatigue items. CONCLUSION: Our results did not provide empirical support for a four or five (bi-)factor structure of the MFI, nor for an alternative model. The most reliable scale of the MFI seems to be the general fatigue scale that could be used as a general indicator of fatigue.

The role of routine follow-up visits of prostate cancer survivors in addressing supportive care and information needs: a qualitative observational study.

PURPOSE: To understand the role of routine follow-up visits in addressing prostate cancer survivors' supportive care and information needs. METHODS: We audio-recorded follow-up visits of 32 prostate cancer survivors. Follow-up visits were analyzed according to the Verona Network of Sequence Analysis. We categorized survivors' cues, concerns, and questions into five supportive care domains and divided the responses by the healthcare professionals into providing versus reducing space that is to determine whether or not the response invites the patient to talk more about the expressed cue or concern. RESULTS: Prostate cancer survivors mostly expressed cues, concerns, and questions (in the health system and information domain) about test results, potential impotence treatment, follow-up appointments, and (their) cancer treatment during follow-up visits. Survivors also expressed urinary complaints (physical and daily living domain) and worry about the recurrence of prostate cancer (psychological domain). Healthcare professionals were two times more likely to provide space on cues and concerns related to the physical and daily living domain than to psychological related issues. CONCLUSION: Follow-up visits can serve to address prostate cancer survivors' supportive care and information needs, especially on the health system, information, and physical and daily living domain. Survivors also expressed problems in the psychological domain, although healthcare professionals scarcely provided space to these issues. We would like to encourage clinicians to use these results to personalize follow-up care. Also, these data can be used to develop tailored (eHealth) interventions to address supportive care and information needs and to develop new models of survivorship care delivery.

Coping with social consequences of disease-related symptoms in patients with a metastatic small intestinal neuroendocrine tumour: A qualitative study.

Patients with small intestine neuroendocrine tumours (SINETs) face various disease-related symptoms that can affect their social functioning and quality of life. The present study aimed to explore the social consequences of disease-related symptoms in patients with a metastatic SINET and to develop a theory on how these patients experience their disease. Patients were eligible when they were diagnosed with a metastatic SINET between 2009 and 2016 and were younger than 60 years of age during diagnosis, and had a good functional performance status. Semi-structured interviews were conducted between January and June 2018. Data were transcribed and analysed independently by two researchers using grounded theory. Data saturation was reached at 10 interviews and, in total, 12 patients participated. A core component that arose from the interviews was resilience in the face of social consequences of having a metastatic SINET. Prominent physical symptoms were fatigue, diarrhoea and flushes. All of these symptoms were associated with limitations to function in work-related and social activities, as well as feelings of embarrassment and shame. Adaptive strategies, such as careful planning, or focusing on the perspective to live well with a neuroendocrine tumour, helped patients to experience the consequences as less burdensome. Other helpful factors that were identified constituted social support, engaging in meaningful activities and financial stability. Patients with a metastatic SINET experienced social consequences of disease-related symptoms in daily life, although they were able to attenuate the burden of these consequences by using adaptive problem-based, emotion-based and meaning-based coping strategies. Clinicians could explore the perceived consequences and educate patients about adaptive strategies.

Design of the PROstate cancer follow-up care in Secondary and Primary hEalth Care study (PROSPEC): a randomized controlled trial to evaluate the effectiveness of primary care-based follow-up of localized prostate cancer survivors.

BACKGROUND: In its 2006 report, From cancer patient to cancer survivor: lost in transition, the U.S. Institute of Medicine raised the need for a more coordinated and comprehensive care model for cancer survivors. Given the ever increasing number of cancer survivors, in general, and prostate cancer survivors, in particular, there is a need for a more sustainable model of follow-up care. Currently, patients who have completed primary treatment for localized prostate cancer are often included in a specialist-based follow-up care program. General practitioners already play a key role in providing continuous and comprehensive health care. Studies in breast and colorectal cancer suggest that general practitioners could also consider to provide survivorship care in prostate cancer. However, empirical data are needed to determine whether follow-up care of localized prostate cancer survivors by the general practitioner is a feasible alternative. METHODS: This multicenter, randomized, non-inferiority study will compare specialist-based (usual care) versus general practitioner-based (intervention) follow-up care of prostate cancer survivors who have completed primary treatment (prostatectomy or radiotherapy) for localized prostate cancer. Patients are being recruited from hospitals in the Netherlands, and randomly (1:1) allocated to specialist-based (N = 195) or general practitioner-based (N = 195) follow-up care. This trial will evaluate the effectiveness of primary care-based follow-up, in comparison to usual care, in terms of adherence to the prostate cancer surveillance guideline for the timing and frequency of prostate-specific antigen assessments, the time from a biochemical recurrence to retreatment decision-making, the management of treatment-related side effects, health-related quality of life, prostate cancer-related anxiety, continuity of care, and cost-effectiveness. The outcome measures will be assessed at randomization (≤6 months after treatment), and 12, 18, and 24 months after treatment. DISCUSSION: This multicenter, prospective, randomized study will provide empirical evidence regarding the (cost-) effectiveness of specialist-based follow-up care compared to general practitioner-based follow-up care for localized prostate cancer survivors. TRIAL REGISTRATION: Netherlands Trial Registry, Trial NL7068 (NTR7266). Prospectively registered on 11 June 2018.

The risk of developing cardiovascular disease is increased for patients with prostate cancer who are pharmaceutically treated for depression.

OBJECTIVE: To examine the associations between pharmaceutically treated anxiety and depression and incident cardiovascular disease (CVD) among 1-year prostate cancer survivors. PATIENTS AND METHODS: A registry-based cohort study design was used to describe the risk of incident CVD in adult 1-year prostate cancer survivors without a history of CVD. Patients with prostate cancer diagnosed between 1999 and 2011 were selected from the Netherlands Cancer Registry. Drug dispenses were retrieved from the PHARMO Database Network and were used as proxy for CVD, anxiety, and depression. Data were analysed using Cox regression analysis to examine the risk associations between pharmaceutically treated anxiety and depression entered as a time-varying predictor with incident CVD in 1-year prostate cancer survivors, while controlling for age, traditional CVD risk factors, and clinical characteristics. RESULTS: Of the 5262 prostate cancer survivors, 327 (6%) developed CVD during the 13-year follow-up period. Prostate cancer survivors who were pharmaceutically treated for depression had an increased risk of incident CVD after full adjustment compared to prostate cancer survivors who were not pharmaceutically treated for depression (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.06-2.15). The increased risk of incident CVD amongst those pharmaceutically treated for depression compared to those who were not pharmaceutically treated for depression, was only valid among: prostate cancer survivors who were aged ≤65 years (HR 2.91; 95% CI 1.52-5.55); those who were not treated with radiotherapy (HR 1.63; 95% CI 1.01-2.65); those who were treated with hormones (HR 1.76; 95% CI 1.09-2.85); those who were not operated upon (HR 1.55; 95% CI 1.07-2.25); and those with tumour stage III (HR 2.21; 95% CI 1.03-4.74) and stage IV (HR 2.47; 95% CI 1.03-5.89). CONCLUSION: Patients with prostate cancer who were pharmaceutically treated for depression had a 51% increased risk of incident CVD after adjustment for anxiety, age, traditional CVD risk factors, and clinical characteristics. The results emphasise the need to pay attention to (pharmaceutically treated) depressed patients with prostate cancer prior to deciding on prostate cancer treatment and for a timely detection and treatment of CVD.

Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have become a standard of care option for the treatment of patients with advanced melanoma. Since the approval of the first immune checkpoint (CTLA-4) inhibitor ipilimumab in 2011 and programmed death-1 (PD-1) blocking monoclonal antibodies pembrolizumab and nivolumab thereafter, an increasing proportion of patients with unresectable advanced melanoma achieved long-term overall survival. Little is known about the psychosocial wellbeing, neurocognitive function, and quality of life (QOL) of these survivors. Knowledge about the long term side-effects of these novel treatments is scarce as long-term survivorship is a novel issue in the field of immunotherapy. The purpose of this review is to summarize our current knowledge regarding the survival and safety results of pivotal clinical trials in the field of advanced melanoma and to highlight potential long-term consequences that are likely to impact psychosocial wellbeing, neurocognitive functioning, and QOL. The issues raised substantiate the need for clinical investigation of these issues with the aim of optimizing comprehensive health care for advanced melanoma survivors.

Advanced Practice Providers and Survivorship Care: They Can Deliver.

INTRODUCTION: As the number of cancer survivors grows, new models of survivorship care are being implemented, but there is limited evaluation to date. This retrospective review assesses the concordance of care provided to adult-onset cancer survivors by advanced practice providers (nurse practitioners and physician assistants) with Institute of Medicine guidelines for survivorship care. METHODS: Records from three survivorship clinics at a single institution were reviewed for frequency of recurrence surveillance, screening for second cancers, symptom management (physical, psychological), health promotion education (alcohol, tobacco, cholesterol, and bone density screenings; diet/exercise discussion), care coordination, and provision of care plan. Data were characterized using descriptive statistics. RESULTS: Over 2 years, 9,052 unique survivorship visits occurred; 210 breast, 208 prostate, and 204 colorectal visits were randomly selected for review. All patients with breast cancer underwent surveillance for recurrence; 99% were screened for new cancers. Discussion of health promotion activities ranged from 83% to 100%; 91% of patients were reviewed for physical symptoms, and 93% were reviewed for psychological symptoms. All patients with prostate cancer underwent recurrence surveillance; 97% were screened for new primaries. Health promotion activities ranged from 70% to 97%, and symptoms were discussed in 89% of visits. All patients with colorectal cancer underwent a surveillance colonoscopy for recurrence; 97% had a carcinoembryonic antigen test. Among women, 97% had mammograms, and 96% had a Papanicolaou test; 83% of men had a prostate-specific antigen test. Health promotion activities ranged from 69% to 100%, and symptoms were discussed in 93% to 97% of visits. CONCLUSIONS: Findings suggest that advanced practice providers can provide survivorship care in accordance with Institute of Medicine standards, which provide a normative standard. This assessment is an important step in evaluating survivorship outcomes.

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens.

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies.

Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Treatment with chemotherapy, radiotherapy, or surgery that involves reproductive organs can cause impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male pubertal, adolescent, and young adult cancer survivors. Guidelines for surveillance and management of potential adverse effects could improve cancer survivors' health and quality of life. Surveillance recommendations vary considerably, causing uncertainty about optimum screening practices. This clinical practice guideline recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium, developed using evidence-based methodology, critically synthesises surveillance recommendations for gonadotoxicity in male childhood, adolescent, and young adult (CAYA) cancer survivors. The recommendations were developed by an international multidisciplinary panel including 25 experts in relevant medical specialties, using a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. The guidelines reveal the paucity of high-quality evidence, highlighting the need for further targeted research.

Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab. INTERVENTIONS: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003). CONCLUSIONS AND RELEVANCE: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00459771.

A survivorship care plan for breast cancer survivors: extended results of a randomized clinical trial.

PURPOSE: Prevailing wisdom suggests that implementation of a survivorship care plan (SCP) will address deficits in survivorship care planning and delivery for cancer patients. Here, we present 24-month results of a randomized clinical trial on health service and patient-reported outcomes among breast cancer patients transferred to their primary care physician for follow-up care. The 24-month assessments represent the long-term benefit and sustainability of the implantation of a SCP. METHODS: In all, 408 patients with early-stage breast cancer were randomized to the SCP or control group. Patient self-completed questionnaires, supplemented with telephone interviews, during the 24-month study period assessed health service and patient-reported outcomes. The primary outcome was cancer-specific distress. Secondary outcomes included health-related quality of life, patient satisfaction, continuity and coordination of care, and health service outcomes such as adherence to guidelines. RESULTS: Over the course of 24 months, there were no differences between both groups in health service and patient-reported outcomes. Women from Quebec compared to those from Western Canada (p < 0.001), women within 2 years of completion of primary treatment compared to a longer period (p = 0.013), and those with a higher SF-36 mental component score compared to a lower score (p = 0.044) were positively associated with adherence to guidelines. CONCLUSION: The implementation of a SCP in the transition of survivorship care from cancer center to primary care did not contribute to improved health service or patient-reported outcomes in this study population. Therefore, additional research is needed before widespread implementation of a SCP in clinical practice. IMPLICATIONS OF CANCER SURVIVORS: The transition of survivorship care from cancer center to the primary care setting showed no negative effect on health service and patient-reported outcomes.

I-123-MIBG myocardial imaging in trastuzumab-based cardiotoxicity: the first experience.

INTRODUCTION: Cardiotoxicity related to trastuzumab anticancer treatment poses a diagnostic challenge at early stages. The aim of the present pilot study was to assess the value of iodine-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy in breast cancer patients treated with trastuzumab who showed a decrease in their cardiac function. MATERIALS AND METHODS: I-123-MIBG scintigraphy was performed in nine patients with decreased or significantly decreasing left ventricular ejection fraction (LVEF) during trastuzumab therapy. On the basis of planar images, 4 h heart-to-mediastinum (HMR) ratio and washout percentages (WR) were calculated. RESULTS: I-123-MIBG scintigraphy revealed abnormal 4 h HMR and increased WR in three patients. LVEF recovery was observed in none of these patients during 3, 6, and 13 months of follow-up. In two of five patients with normal 4 h HMR the washout rates were also normal, whereas in three patients slightly increased washout rates were found. All five patients demonstrated a recovery of their LVEF value during follow-up. One patient with a normal 4 h HMR and normal WR initially showed a significant decrease in LVEF, which decreased further during follow-up. However, the LVEF value remained at 53%, which was within normal limits, after trastuzumab administration. CONCLUSION: In this pilot study we have explored the role of I-123-MIBG scintigraphy in the assessment of trastuzumab-related cardiotoxicity and suggest that, in patients with a persistently decreasing LVEF, I-123-MIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated.

Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Therapies for breast cancer may induce hot flashes that can affect quality of life. We undertook a double-blind, placebo-controlled trial with the primary objective of comparing the average daily hot flash scores in the twelfth week among patients treated with venlafaxine, clonidine, and placebo. Additional analyses of the hot flash score over the full 12 weeks of treatment were performed. PATIENTS AND METHODS: In all, 102 patients with a history of breast cancer were randomly assigned (2:2:1) to venlafaxine 75 mg, clonidine 0.1 mg, or placebo daily for 12 weeks. Questionnaires at baseline and during treatment assessed daily hot flash scores, sexual function, sleep quality, anxiety, and depression. RESULTS: After 12 weeks, a total of 80 patients were evaluable for the primary end point. During week 12, hot flash scores were significantly lower in the clonidine group versus placebo (P = .03); for venlafaxine versus placebo, the difference was borderline not significant (P = .07). However, hot flash scores were equal in the clonidine and venlafaxine groups. Over the course of 12 weeks, the differences between both treatments and placebo were significant (P <.001 for venlafaxine v placebo; P = .045 for clonidine v placebo). Frequencies of treatment-related adverse effects of nausea (P = .02), constipation (P = .04), and severe appetite loss were higher in the venlafaxine group. CONCLUSION: Venlafaxine and clonidine are effective treatments in the management of hot flashes in patients with breast cancer. Venlafaxine resulted in a more immediate reduction of hot flash scores when compared with clonidine; however, hot flash scores at week 12 were lower in the clonidine group than in the venlafaxine group.