Potential Adverse Outcomes of Shared Decision Making about Palliative Cancer Treatment: A Secondary Analysis of a Randomized Trial.

BACKGROUND: While shared decision making (SDM) is advocated for ethical reasons and beneficial outcomes, SDM might also negatively affect patients with incurable cancer. The current study explored whether SDM, and an oncologist training in SDM, are associated with adverse outcomes (i.e., patient anxiety, tension, helplessness/hopelessness, decisional uncertainty, and reduced fighting spirit). DESIGN: A secondary analysis of a randomized clinical trial investigating the effects of SDM interventions in the context of advanced cancer. The relations between observed SDM (OPTION12), specific SDM elements (4SDM), oncologist SDM training, and adverse outcomes were analyzed. We modeled adverse outcomes as a multivariate phenomenon, followed by univariate regressions if significant. RESULTS: In total, 194 patients consulted by 31 oncologists were included. In a multivariate analysis, observed SDM and adverse outcomes were significantly related. More specifically, more observed SDM in the consultation was related to patients reporting more tension (P = 0.002) and more decisional uncertainty (P = 0.004) at 1 wk after the consultation. The SDM element "informing about the options" was especially found to be related to adverse outcomes, specifically to more helplessness/hopelessness (P = 0.002) and more tension (P = 0.016) at 1 wk after the consultation. Whether the patient consulted an oncologist who had received SDM training or not was not significantly related to adverse outcomes. No relations with long-term adverse outcomes were found. CONCLUSIONS: It is important for oncologists to realize that for some patients, SDM may temporarily be associated with negative emotions. Further research is needed to untangle which, when, and how adverse outcomes might occur and whether and how burden may be minimized for patients. HIGHLIGHTS: Observed shared decision making was related to more tension and uncertainty postconsultation in advanced cancer patientsHowever, training oncologists in SDM did not affect adverse outcomes.Further research is needed to untangle which, when, and how adverse outcomes might occur and how burden may be minimized.

Study protocol of the GLOW study: maximising treatment options for recurrent glioblastoma patients by whole genome sequencing-based diagnostics-a prospective multicenter cohort study.

BACKGROUND: Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. METHODS: The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. DISCUSSION: The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186064.

Attitudes Toward Striving for Quality and Length of Life Among Patients With Advanced Cancer and a Poor Prognosis.

PURPOSE: When deliberating palliative cancer treatment, insight into patients' attitudes toward striving for quality of life (QL) and length of life (LL) may facilitate goal-concordant care. We investigated the (1) attitudes of patients with advanced cancer toward striving for QL and/or LL and whether these change over time, and (2) characteristics associated with these attitudes (over time). METHODS: We performed a secondary analysis of a randomized controlled trial on improving shared decision making (SDM), without differentiation between intervention arms. Patients (n = 173) with advanced cancer, a median life expectancy of < 12 months without anticancer treatment, and a median survival benefit of < 6 months from systemic therapy were included in seven Dutch hospitals. We used audio-recorded consultations and surveys at baseline (T0), shortly after the consultation (T2), at 3 and 6 months (T3 and T4). Primary outcomes were patients' attitudes toward striving for QL and LL (Quality Quantity Questionnaire; T2, T3, and T4). RESULTS: Overall, patients' attitudes toward striving for QL became less positive over 6 months (P < .01); attitudes toward striving for LL did not change on group level. Studying individual patients, 76% showed changes in their attitudes toward striving for QL and/or LL at some point during the study, which occurred in various directions. More helplessness/hopelessness (P < .001), less fighting spirit (P < .05), less state anxiety (P < .001), and more observed SDM (P < .05) related to more positive attitudes toward striving for QL. Lower education, less helplessness/hopelessness, more fighting spirit, and more state anxiety (P < .001) related to more positive attitudes toward striving for LL. CONCLUSION: Oncologists may explore patients' attitudes toward striving for QL and LL repeatedly and address patients' coping style and emotions during SDM to facilitate goal-concordant care throughout the last phase of life.

Effect of a Skills Training for Oncologists and a Patient Communication Aid on Shared Decision Making About Palliative Systemic Treatment: A Randomized Clinical Trial.

BACKGROUND: Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM. METHODS: In this multicenter randomized controlled trial with four parallel arms (2016-2018), oncologists (n = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients (n = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio-recorded consultations. Secondary outcomes included patient-reported SDM, patient and oncologist satisfaction, patients' decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made. RESULTS: The oncologist training had a large positive effect on observed SDM (Cohen's d = 1.12) and on patient-reported SDM (d = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients' decisional conflict, quality of life, consultation duration, or the decision made. CONCLUSION: Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient-reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice. TRIAL REGISTRATION: Netherlands Trial Registry NTR 5489. IMPLICATIONS FOR PRACTICE: Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient-reported SDM in clinical encounters (n = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists' practice and should be implemented in (continuing) educational programs.

Everolimus Reduces (89)Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors.

UNLABELLED: Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. METHODS: Patients with advanced progressive well-differentiated NETs underwent (89)Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. (89)Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). RESULTS: In 4 of the 14 patients entered, no tumor lesions were visualized with (89)Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of -7% at 2 wk (P = 0.09) and a median of -35% at 12 wk (P < 0.001). The difference in SUVmax at 2 and 12 wk with respect to SUVmax at baseline correlated with percentage change on CT at 6 mo (r(2) = 0.51, P < 0.05, and r(2) = 0.61, P < 0.01, respectively). CONCLUSION: This study demonstrates variable (89)Zr-bevacizumab PET tumor uptake in NET patients. (89)Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial (89)Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGF-directed treatment in NET patients.

Tailored imaging of islet cell tumors of the pancreas amidst increasing options.

Pancreatic islet cell tumors are neuroendocrine tumors, which can produce hormones and can arise as part of multiple endocrine neoplasia type 1 or von-Hippel-Lindau-disease, two genetically well-defined hereditary cancer syndromes. Currently, technical innovation improves conventional and specific molecular imaging techniques. To organize the heterogeneous results described for the imaging of these tumors, we distinguished three indications (1) imaging of a patient with hormone hypersecretion, (2) search for a pancreatic primary in case of proven neuroendocrine cancer of unknown primary, and (3) screening of asymptomatic mutation carriers. We searched for publications on imaging of islet cell tumors between 1995 and January 2010 and defined a Level of Evidence (LOE) for the applicability of each technique. For each technique, data were analyzed in a Forest plot and arranged per imaging indication and tumor subtype. LOEs are weak for all imaging techniques. Analyses indicate a prominent role for endoscopic ultrasound for all three indications.

Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour.

PURPOSE: Positron emission tomography (PET) using 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. METHODS: Seventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. RESULTS: All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r=0.51) and urinary and plasma 5-HIAA (r=0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. CONCLUSION: Tumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity.

Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues.

BACKGROUND: Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms. METHODS: Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 µg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹8F]fluoro-2-deoxy-d-glucose positron emission tomography (¹8F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹8F-FDG uptake was quantified as the maximum standardized uptake value. RESULTS: All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹8F-FDG uptake. Everolimus reduced tumor and muscle ¹8F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%. CONCLUSIONS: Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

6-[F-18]Fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computer tomography, and magnetic resonance imaging in localizing tumors causing catecholamine excess.

CONTEXT: Catecholamine excess is rare, but symptoms may be life threatening. OBJECTIVE: The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET), compared with (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess. DESIGN AND SETTING: All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible. PATIENTS: Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three. MAIN OUTCOME MEASURES: Sensitivities and discordancy between (18)F-DOPA PET, (123)I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of (18)F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard. RESULTS: (18)F-DOPA PET showed lesions in 43 patients, (123)I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for (18)F-DOPA PET, (123)I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 1.0 (123)I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 0.51 (123)I-MIBG vs. CT/MRI). The combination of (18)F-DOPA PET with CT/MRI was superior to (123)I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with (18)F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57). CONCLUSION: To localize tumors causing catecholamine excess, (18)F-DOPA PET is superior to (123)I-MIBG scintigraphy and CT/MRI.

Combining 6-fluoro-[18F]l-dihydroxyphenylalanine and [18F]fluoro-2-deoxy-d-glucose positron emission tomography for distinction of non-carcinoid malignancies in carcinoid patients.

AIM: Carcinoid patients frequently develop a second primary malignancy (SPM), which can deserve full treatment. Distinguishing a SPM from carcinoid lesions is therefore important. Differentiation can be achieved using the difference in uptake between different positron emission tomography (PET) tracers. METHODS AND RESULTS: Between January 2005 and August 2008, 105 carcinoid patients were seen at the Department of Medical Oncology for treatment and follow-up. We identified 3 patients who presented with a new SPM in whom differentiation between carcinoid lesions and the SPM was guided by functional imaging of the catecholamine pathway with 6-fluoro-[(18)F]l-dihydroxyphenylalanine ((18)F-DOPA) PET and [(18)F]fluoro-2-deoxy-d-glucose ((18)F-FDG) PET as radiotracer for the glucose metabolism. All 3 patients had metastatic carcinoid disease and localised adenocarcinoma based on the PET-scans. For the adenocarcinoma they received curative treatment. CONCLUSION: The difference in uptake between these PET techniques can be used for decision making when a primary or metastatic SPM is suspected.