Cancer survivors' experiences of a physical activity program in primary care: a qualitative study.

PURPOSE: This study aimed to gain insight into the experiences of, and reasons for, cancer survivors participating in a primary care PA program. METHODS: We interviewed 17 patients from 11 Dutch GP practices. Patients were selected by purposive sampling based on their general practice, gender, educational level, motivation for PA, and change in PA. Interviews were audio recorded, transcribed verbatim, and pseudonymized for inductive thematic analysis. RESULTS: Three domains were identified with five themes: institutional domain: GP practice; program-specific domain: content sessions and PA, and activity tracker and goal setting; individual domain: experienced benefits, and personalized care needs. Participants valued the PA program because it was offered close to home, without additional costs, and by a trusted practice nurse familiar with the patients' medical background. Activity tracker use and goal setting motivated many participants but also led to demotivation and feelings of failure in others. Reported benefits included behavior change and favorable health outcomes. Many patients expressed the need to personalize psychological support and the program's timing. CONCLUSIONS: Access to a PA program in a primary care setting is valued for its accessibility and experienced health benefits, but also seems to meet an unmet need for support in picking up life during cancer recovery. IMPLICATIONS FOR CANCER SURVIVORS: Primary care is important for continued care of cancer survivors. An accessible PA program in this setting may fulfil a need for not only lifestyle support but also continuing life after cancer treatment.

Physical exercise in patients with testicular cancer treated with bleomycin, etoposide and cisplatin chemotherapy: pulmonary and vascular endothelial function-an exploratory analysis.

PURPOSE: Bleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially life-threatening toxicities like pneumonitis and thromboembolic events. This study explored the effects of physical exercise in patients with testicular cancer during or after BEP-chemotherapy on pulmonary and vascular endothelial toxicity. METHODS: In this post hoc analysis of a multicenter randomized clinical trial (NCT01642680), patients with metastatic testicular cancer scheduled to receive BEP-chemotherapy were randomized to a 24-week exercise intervention, initiated during (group A) or after BEP-chemotherapy (group B). Endpoints were pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), lung transfer-coefficient and transfer factor for carbon monoxide (KCO, DLCO) and markers of vascular endothelial dysfunction (von Willebrand factor (vWF) and factor VIII). RESULTS: Thirty patients were included. Post-chemotherapy, patients declined less in FVC, FEV1 and DLCO in group A compared to group B. Post-chemotherapy, vWF and factor VIII were significantly lower in group A compared to group B. After completion of exercise, started either during BEP-chemotherapy or thereafter, no between-group differences were found. At 1-year post-intervention, significant between-group differences were found in favour of group A in DLCO and KCO. CONCLUSIONS: Patients who exercised during BEP-chemotherapy better preserved FVC, FEV1 and DLCO, measured directly post-chemotherapy and 1-year post-intervention (DLCO, KCO). This coincided with less increase in vWF and factor VIII measured directly post-chemotherapy. These data support a beneficial role of a physical exercise intervention during BEP-chemotherapy on pulmonary and vascular damage in patients with testicular cancer. TRIAL REGISTRY: Optimal Timing of Physical Activity in Cancer Treatment (ACT) Registry URL: https://clinicaltrials.gov/ct2/show/NCT01642680 . TRIAL REGISTRATION NUMBER: NCT01642680.

Optimal Timing of a Physical Exercise Intervention to Improve Cardiorespiratory Fitness: During or After Chemotherapy.

Background: Despite the widely acknowledged benefit of exercise for patients with cancer, little evidence on the optimal timing of exercise on adverse effects of cancer treatment is available. Objectives: The aim of this study was to determine whether an exercise intervention initiated during chemotherapy is superior to an intervention initiated after chemotherapy for improving long-term cardiorespiratory fitness (peak oxygen uptake [VO2peak]). Methods: In this prospective, randomized clinical trial, patients scheduled to receive curative chemotherapy were randomized to a 24-week exercise intervention, initiated either during chemotherapy (group A) or afterward (group B). The primary endpoint was VO2peak 1 year postintervention. Secondary endpoints were VO2peak postintervention, muscle strength, health-related quality of life (HRQoL), fatigue, physical activity, and self-efficacy. Between-group differences were calculated using intention-to-treat linear mixed-models analyses. Results: A total of 266 patients with breast (n = 139), testicular (n = 95), and colon cancer (n = 30) as well as lymphoma (n = 2) were included. VO2peak immediately postintervention and 1 year postintervention did not differ between the 2 groups. Immediately postchemotherapy, patients in group A exhibited significantly lower decreases in VO2peak (3.1 mL/kg/min; 95% CI: 2.2-4.0 mL/kg/min), HRQoL, and muscle strength and reported less fatigue and more physical activity than those in group B. Conclusions: Exercise can be safely performed during chemotherapy and prevents fatigue and decreases in VO2peak, muscle strength, and HRQoL, in addition to hastening the return of function after chemotherapy. Also, if exercise cannot be performed during chemotherapy, a program afterward can enable patients to regain the same level of function, measured 1 year after completion of the intervention. (Optimal Timing of Physical Activity in Cancer Treatment [ACT]; NCT01642680).

Long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: A population-based study.

BACKGROUND: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) comprise a group of rare malignant tumours with heterogeneous behaviour. This study aimed to assess long-term survival and prognostic factors associated with survival, in order to optimise counselling. PATIENTS AND METHODS: This population-based study included all GEP-NENs diagnosed between 1989 and 2016 in the Netherlands, selected from the Netherlands Cancer Registry. Overall survival (OS) and relative survival (RS) were calculated. A Cox Proportional Hazard analysis was used to identify prognostic factors (gender, age, tumour stage, location and treatment) for OS. Analyses were stratified by metastatic disease status and tumour grade. RESULTS: In total, 9697 patients were included. In grade 1, 2 and 3 non-metastatic GEP-NENs (N = 6544), 5-year OS and RS were 81% and 88%, 78% and 83%, and 26% and 30%, respectively. In grade 1 non-metastatic GEP-NENs 10-year OS and RS were 68% and 83%. In grade 1, 2 and 3 metastatic GEP-NENs (N = 3153), 5-year OS and RS rates were 47% and 52%, 38% and 41%, and 5% and 5%, respectively. The highest (relative) survival rates were found in appendicular and rectal NENs, demonstrating 10-year OS and RS of 87% and 93%, and 81% and 95%, respectively. CONCLUSIONS: These long-term follow-up data demonstrate significant differences in survival for different grades, tumour stage, and primary origin of GEP-NENs, with the most favourable overall and RS rates in patients with non-metastatic grade 1 appendicular and rectal NENs. This study demonstrates unique long-term OS and RS rates using combined stratification by tumour site, grade and stage.

Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors: A Cross-Sectional Study.

Background: Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear. Objectives: The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors. Methods: We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders. Results: In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (ß = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity. Conclusions: In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors.

Comparison of [18F]DOPA and [68Ga]DOTA-TOC as a PET imaging tracer before peptide receptor radionuclide therapy.

BACKGROUND: In treatment of neuroendocrine neoplasms (NENs), confirmation of somatostatin receptor expression with 68Ga-DOTA somatostatin analogues is mandatory to determine eligibility for peptide receptor radionuclide therapy (PRRT). [18F]DOPA can detect additional lesions compared to [68Ga]DOTA-TOC. The aim of this study was to explore differences in tumour detection of both tracers and their relevance for selecting patients for PRRT. We retrospectively studied eight patients with NENs who underwent both [68Ga]DOTA-TOC and carbidopa-enhanced [18F]DOPA PET/CT, before first-time PRRT with [177Lu]DOTA-TATE. Tracer order was influenced due to stock availability or to detect suspected metastases with a second tracer. On CT, disease control was defined as a lesion showing complete response, partial response, or stable disease, according to RECIST 1.1. RESULTS: Seven patients with in total 89 lesions completed four infusions of 7.4 GBq [177Lu]DOTA-TATE, one patient received only two cycles. Before treatment, [18F]DOPA PET/CT detected significantly more lesions than [68Ga]DOTA-TOC PET/CT (79 vs. 62, p < .001). After treatment, no difference in number of lesions with disease control was found for [18F]DOPA-only (5/27) and [68Ga]DOTA-TOC-only lesions (4/10, p = .25). [18F]DOPA detected more liver metastases (24/27) compared to [68Ga]DOTA-TOC (7/10, p = .006). Six patients showed inpatient heterogeneity in treatment response between [18F]DOPA-only and [68Ga]DOTA-TOC-only lesions. CONCLUSIONS: Response to PRRT with [177Lu]DOTA-TATE was comparable for both [68Ga]DOTA-TOC- and [18F]DOPA-only NEN lesions. [18F]DOPA may be capable of predicting response to PRRT while finding more lesions compared to [68Ga]DOTA-TOC, although these additional lesions are often small of size and undetected by diagnostic CT.

Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Risk factors for complications after surgery for pancreatic neuroendocrine tumors.

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors. METHODS: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3). RESULTS: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029). CONCLUSION: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications.

Implementation and evaluation of a physical activity counselling programme in primary care among cancer survivors: SoDA study protocol.

INTRODUCTION: Physical activity (PA) favourably affects various health outcomes in cancer survivors, but little is known about how to implement a PA programme in primary care. We therefore aim to implement and evaluate such a programme for cancer survivors in general practice. METHODS AND ANALYSES: The Stimulation of Daily Activity study is an implementation study with a single-arm longitudinal design in 15 Dutch general practices. Patients aged ≥18 years who finished cancer treatment more than 6 months ago will be eligible for inclusion. The intervention will comprise six coaching sessions with the practice nurse in 9 months, seeking to increase PA in daily activities and using an activity tracker for goal setting and feedback. The Reach, Effectiveness, Adoption, Implementation and Maintenance framework will be used to evaluate implementation in terms of the health outcomes, extent of implementation and barriers and facilitators to implementation, using a mixed methods approach. Descriptive analyses and linear mixed model analyses will be performed on the quantitative data, while qualitative data from focus groups and interviews will be analysed by thematic analyses. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of the University Medical Centre Groningen, the Netherlands, concluded that this study was not subject to the Dutch Medical Research Involving Human Subjects Act (registration number: 201900586). The study results will be made available to patients and general practitioners via (inter)national publications and conferences, newsletters, public summaries and via (social) media.

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7-291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79-35.9], 7.7% (95% CI, 1.17-50.6), and 17% (95% CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0-27.0); C: 7.7% (95% CI, 0.2-36.0); D: 10% (95% CI, 2.1-26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88). CONCLUSIONS: At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.

The EGFRvIII transcriptome in glioblastoma: A meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being among its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signaling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged 4 large datasets into 1 large glioblastoma transcriptome dataset (n = 741) alongside 81 whole-genome samples from 2 datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumors and range from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII-positive and -negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (P = .007), which may point toward crosstalk between these pathways. EGFRvIII-expressing tumors have an upregulation of "classical" subtype genes compared to those with EGFR-amplification only (P = 3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference toward the 3'-end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumors.

Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment.

BACKGROUND: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls. METHODS: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)-with a follow-up duration ≥ 20 years-and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs). RESULTS: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20-42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score -0.85; 95% CI -1.39 to -0.33) compared to controls (mean 0.67; 95% CI -0.21 to 1.57, p < 0.01). In univariate analysis, the presence of hypogonadism (ß -1.50, p < 0.01), high c-PWV (ß -0.35, p = 0.09), and high AGEs (ß -1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (ß -1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p < 0.01). CONCLUSIONS: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. TRIAL REGISTRATION: NCT02572934.

Home-based Physical Activity to Alleviate Fatigue in Cancer Survivors: A Systematic Review and Meta-analysis.

PURPOSE: Physical activity (PA) affects fatigue and mental health in cancer survivors favorably, but participation in PA interventions tends to be low. More participants may be reached by home-based PA owing to greater accessibility and self-monitoring. This systematic review therefore evaluated the effects of home-based PA of low to moderate intensity on symptoms of fatigue, depression, and anxiety among cancer survivors. METHODS: PubMed, CINAHL, PsycINFO, and Web of Science were systematically searched for randomized controlled trials. We included investigations of home-based PA interventions in adults treated curatively for cancer and evaluating fatigue, depression, or anxiety as outcomes. We performed a random-effect meta-analysis for the effects of PA interventions on fatigue in the short and long terms. Subgroup analyses were performed for the frequency of counseling. Standardized mean differences (SMD) and 95% confidence intervals are reported. RESULTS: Eleven articles comprising 1066 participants were included: 77% had a history of breast cancer; 14%, ovarian cancer; 4%, colorectal cancer; 4%, prostate cancer; and 1%, "other" cancer (not specified). Concerning the outcomes, nine articles reported on fatigue and two reported on depression or anxiety. Meta-analyses showed a significant effect of home-based PA on fatigue immediately after the intervention (SMD = 0.22 [0.06-0.37]), at 3 months' follow-up (SMD = 0.27 [0.04-0.51]), and at 6-9 months' follow-up (SMD = 0.31 [0.08-0.55]). PA interventions that used frequent counseling were associated with larger improvements in fatigue than those using no or infrequent counseling. CONCLUSIONS: Home-based PA interventions can reduce fatigue among adult cancer survivors for up to 9 months, and frequent counseling may improve the benefits of these interventions.

The effects of molar activity on [18F]FDOPA uptake in patients with neuroendocrine tumors.

BACKGROUND: 6-[18F]fluoro-L-3,4-dihydroxyphenyl alanine ([18F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [18F]FDOPA is decarboxylated to [18F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [18F]FDOPA has been developed, [18F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([18F]FDOPA-L). AIMS: This study aimed to investigate whether the difference in molar activity affects the [18F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [18F]FDOPA-H would be equal to or higher than [18F]FDOPA-L. METHODS: We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [18F]FDOPA-H and [18F]FDOPA-L within a time span of 5 years. A total of 98 [18F]FDOPA scans (49 [18F]FDOPA-L and 49 [18F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1-2 lesions) and higher tumor load (3-10 lesions). RESULTS: Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [18F]FDOPA-H compared to [18F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [18F]FDOPA-H group with 3-10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L. CONCLUSION: [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV's, with slight increases in uptake of [18F]FDOPA-H in comparison to [18F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [18F]FDOPA.

Effects of supervised exercise during adjuvant endocrine therapy in overweight or obese patients with breast cancer: The I-MOVE study.

BACKGROUND: Adjuvant endocrine therapy (ET) in patients with breast cancer (BC) increases the risk of becoming less physically active. Physical inactivity is associated with a higher risk of treatment-related side effects and mortality. This study investigated whether supervised exercise increased the proportion of patients adhering to the national physical activity (PA) guideline during adjuvant ET in overweight or obese BC patients. METHODS: This multicentre single-arm clinical trial included patients with BC participating in a 12-week supervised exercise intervention. An accelerometer measured moderate to vigorous PA (MVPA) at baseline (T0), after 12 (T1) and 26 weeks (T2). The primary endpoint was change in the proportion of patients with weekly ≥150 min of MVPA at T1 compared to T0. Secondary endpoints were adherence to PA guideline at T2, metabolic syndrome (MetS), body composition, health-related quality of life (HRQoL) and BC-specific functioning and symptoms, self-reported PA, self-efficacy, exercise motivation and satisfaction with life. RESULTS: 141 patients with a median age of 61 years and a mean BMI of 31.3 participated. Adherence to the PA guideline increased from 38.3% at T0, to 40.4% at T1 (p = .112) and 44.7% at T2 (p = .003). MetS, body composition, HRQoL, BC-specific functioning and symptoms (i.e. fatigue, dyspnoea), self-reported PA, self-efficacy, exercise motivation and satisfaction with life improved significantly over time. CONCLUSIONS: Supervised exercise increased the proportion of BC patients adhering to the PA guideline over time. Furthermore, MetS, body composition, HRQoL and symptoms improved. Our findings highlight the clinical relevance of supervised exercise during ET in overweight BC patients. CLINICAL TRIAL INFORMATION: (NCT02424292).

Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review.

IMPORTANCE: Patients with extrapulmonary neuroendocrine carcinomas (EPNECs) receive essentially the same treatment as those with small cell lung cancer (SCLC) despite differences in origin, clinical course, and survival. This SCLC-based approach is attributable to the rarity of EPNECs, which impedes the use of randomized clinical trials. However, neuroendocrine carcinomas are becoming more common because of the increasing use of systemic cancer therapy for adenocarcinomas. This treatment can transdifferentiate certain adenocarcinomas into neuroendocrine carcinomas. In addition, the treatment landscape for SCLC is slowly changing, potentially impacting the treatment paradigms for EPNECs. OBSERVATIONS: New information on tumorigenesis of EPNECs from different origins, either as a primary malignant tumor or after neuroendocrine differentiation from adenocarcinomas, demonstrates their biological similarity. Activated molecular pathways that appear to underlie the development of EPNECs are potentially targetable, and some of these targets, such as poly(adenosine diphosphate-ribose) polymerase, Wee1, and Aurora A kinase, are currently under investigation. Immune checkpoint inhibitors (ICIs) already constituted a new treatment modality for patients with SCLC and produced some promising results in patients with EPNECs. CONCLUSIONS AND RELEVANCE: Although only moderately effective, the introduction of ICIs signifies the first new option in systemic treatment of SCLC in decades. To prove the value of ICIs and other new drugs for patients with EPNECs, these patients should be included in clinical trials independent of the primary tumor site. Furthermore, to optimize clinical decision-making for patients with EPNECs, experts from the neuroendocrine tumor board should collaborate with members from tumor site-specific boards, which will require patient referral to a center with EPNEC expertise.

Impact of depatuxizumab mafodotin on health-related quality of life and neurological functioning in the phase II EORTC 1410/INTELLANCE 2 trial for EGFR-amplified recurrent glioblastoma.

BACKGROUND: In the EORTC 1410/INTELLANCE 2 randomised, phase II study (NCT02343406), with the antibody-drug conjugate depatuxizumab mafodotin (Depatux-M, ABT-414) in patients with recurrent EGFR-amplified glioblastoma, the primary end-point (overall survival) was not met, and the drug had ocular dose-limiting toxicity. This study reports results from the prespecified health-related quality of life (HRQoL) and neurological deterioration-free survival (NDFS) exploratory analysis. PATIENTS AND METHODS: Patients (n = 260) were randomised 1:1:1 to receive either Depatux-M 1.25 mg/kg or 1.0 mg/kg intravenously every 2 weeks with oral temozolomide (TMZ) 150 mg/m2, Depatux-M alone, or TMZ or oral lomustine (CCNU) 110 mg/m2 (TMZ/CCNU). HRQoL outcomes were recorded using the EORTC core Quality of Life QLQ-C30, and brain cancer-specific QLQ-BN20 questionnaires. Questionnaires were completed at baseline, weeks 8 and 16, and month 6, and changes from baseline to each time point were calculated. NDFS was defined as time to first deterioration in World Health Organisation performance status. RESULTS: Compliance with HRQoL was 88.1% at baseline and decreased to 37.9% at month 6. Differences from baseline between Depatux-M arms and TMZ/CCNU in global health/QoL status throughout treatment did not reach clinical relevance (≥10 points). Self-reported visual disorders deteriorated to a clinically relevant extent with Depatux-M arms versus TMZ/CCNU at all timepoints (mean differences range: 24.6-35.1 points). Changes from baseline for other HRQoL scales and NDFS were generally similar between treatment arms. CONCLUSIONS: Depatux-M had no impact on HRQoL and NDFS in patients with EGFR-amplified recurrent glioblastoma, except for more visual disorders, an expected side-effect of the study drug. CLINICAL TRIAL REGISTRATION: NCT02343406.

At the Bedside: Profiling and treating patients with CXCR4-expressing cancers.

The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx-xx; 2020.

Comparison of 18F-DOPA Versus 68Ga-DOTATOC as Preferred PET Imaging Tracer in Well-Differentiated Neuroendocrine Neoplasms.

PURPOSE: The aim of this study was to retrospectively compare 18F-FDOPA versus 68Ga-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs). PATIENTS AND METHODS: All patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both 18F-DOPA and 68Ga-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before 18F-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on 18F-DOPA (DOPA > DOTA), more lesions on 68Ga-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts. RESULTS: 18F-DOPA revealed significantly more lesions compared with 68Ga-DOTATOC (611 vs 385, P < 0.05). Twenty-four patients were included in the DOPA > DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P < 0.05, and 320 vs 81, P < 0.05, respectively). Cutoff values of 20 nmol/109 for serotonin, 185 µg/L for chromogranin A, and 200 nmol/L for 5-HIAA were found to include almost exclusively DOPA > DOTA patients. CONCLUSIONS: There is an advantage of carbidopa pretreated 18F-DOPA over 68Ga-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the 18F-DOPA PET scan, which requires further prospective analysis.

Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy.

BACKGROUND: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS. METHODS: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). RESULTS: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20-42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10-3 vs. 4.04 × 10-3; p = 0.03). CONCLUSION: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with "accelerated vascular aging" and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT02572934.