A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Enzalutamide is a potent androgen receptor signalling inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. METHODS: This multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale-15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. KEY FINDINGS AND LIMITATIONS: In total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4-11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. CONCLUSIONS AND CLINICAL IMPLICATIONS: A reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. PATIENT SUMMARY: In this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

Baseline effector cells predict response and NKT cells predict pulmonary toxicity in advanced breast cancer patients treated with everolimus and exemestane.

BACKGROUND: The mTOR inhibitor everolimus used in cancer has immune-modulating effects, potentially contributing to an antitumor response but also leading to pulmonary toxicity. We studied the association of immunological cell subsets with antitumor response and pulmonary toxicity in breast cancer patients treated with everolimus plus exemestane. METHODS: In this exploratory analysis, peripheral blood mononuclear cells (PBMCs) were collected at baseline and 14, 35, 60, and 90 days after start of treatment, and at the moment of pulmonary toxicity. The percentage and absolute number of T-cells, B-cells, NK-cells, monocytes and numerous subtypes were measured in peripheral blood using flow cytometric analysis and were compared using a (paired) t-test. RESULTS: From 20 patients, a total of 89 samples were collected. At baseline, responders versus non-responders had 0.86% versus 0.32% CD4+ effector cells (CD45RA+CD27-) (p = 0.1266) and non-response could be predicted with 0.71 sensitivity and 0.82 specificity. Patients who developed pulmonary toxicity compared to patients without pulmonary toxicity had relatively more NKT-cells at baseline (6.0% versus 1.3%, p = 0.0068, 59 k versus 12 k * 109/l, p = 0.0081) and at the moment of toxicity (5.2% versus 1.2%, p = 0.0106 and 47 k versus 16 k * 109/l, p = 0.0466). Baseline percentage NKT cells predicted pulmonary toxicity with 0.78 sensitivity and 1.0 specificity. CONCLUSIONS: Our results suggest that baseline CD4+ effector cells may be predictive of antitumor responses and baseline NKT cells may be predictive of pulmonary toxicity. These results warrant further validation.

Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane.

BACKGROUND: Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. OBJECTIVE: We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. PATIENTS AND METHODS: Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18F-FDG-PET were prospectively recorded. RESULTS: Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimus-related respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. CONCLUSIONS: This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.

Molecular tumour boards and molecular diagnostics for patients with cancer in the Netherlands: experiences, challenges, and aspirations.

Advances in molecular tumour diagnostics and the number of targeted therapies increase rapidly. Molecular tumour boards (MTBs) are designated to interpret these data and provide clinical recommendations. Not all patients with cancer have access to advice of an MTB. We aimed to determine the current status, opportunities, and challenges of the organisation of MTBs in the Netherlands. We interviewed several stakeholders about their experiences with an MTB, using template analysis. Most clinicians and patient representatives underscore the significance of an MTB, because it can stimulate rational treatment options, enrolment in clinical trials, and interdisciplinary knowledge transfer. Health insurance companies and financial managers are concerned about increasing costs. Registries to assess the clinical benefit of MTBs, guidelines on quality control, financial agreements, and logistical resources are lacking. The national organisation of MTBs and a registry of molecular and clinical data are important issues to address.

Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane.

BACKGROUND: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. OBJECTIVE: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. PATIENTS AND METHODS: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). RESULTS: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 µg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 µg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 µg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. CONCLUSIONS: Our results show that everolimus toxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.

Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report.

INTRODUCTION: Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma. CASE PRESENTATION: A 62-year-old man was treated with nivolumab for papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy showed focal segmental glomerulosclerosis. Treatment with high-dose corticosteroids had insufficient effect, but the addition of mycophenolate mofetil resulted in remission of the nephrotic syndrome and recovery of renal function. Proteinuria subsequently relapsed during corticosteroid tapering. CONCLUSIONS: The time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication.

Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors.

Oral targeted therapies represent an increasingly important group of drugs within modern oncology. With the shift from intravenously to orally administered drugs, drug absorption is a newly introduced factor in drug disposition. The process of absorption can have a large effect on inter- and intrasubject variability in drug exposure and thereby potentially treatment benefit or the severity of toxicities. The intake of oral targeted therapies with food and concomitant use of acid-reducing agents (ARAs) can significantly affect drug absorption. The size and direction of the effect of food and ARAs on drug absorption varies among drugs as a result of different chemical characteristics. Therefore, an awareness and understanding of these effects for each drug is essential to optimize patient outcomes.

Positron emission tomography response criteria in solid tumours criteria for quantitative analysis of [18F]-fluorodeoxyglucose positron emission tomography with integrated computed tomography for treatment response assessment in metastasised solid tumours: All that glitters is not gold.

For solid tumours, quantitative analysis of [(18)F]-fluorodeoxyglucose positron emission tomography with integrated computed tomography potentially can have significant value in early response assessment and thereby discrimination between responders and non-responders at an early stage of treatment. Standardised strategies for this analysis have been proposed, and the positron emission tomography response criteria in solid tumours (PERCIST) criteria can be regarded as the current standard to perform quantitative analysis in a research setting, yet is not implemented in daily practice. However, several exceptions and limitations limit the feasibility of PERCIST criteria. In this article, we point out dilemmas that arise when applying proposed criteria like PERCIST on an expansive set of patients with metastasised solid tumours. Clinicians and scientists should be aware of these limitations to prevent that methodological issues impede successful introduction of research data into clinical practice. Therefore, to deliver on the high potential of quantitative imaging, consensus should be reached on a standardised, feasible and clinically useful analysis methodology. This methodology should be applicable in the majority of patients, tumour types and treatments.

mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm.

Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi-induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi-induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi-induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune-mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi-induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm.

[Choosing wisely when prescribing statins]. / Verstandig kiezen bij het voorschrijven van statinen.

The Dutch campaign 'Verstandig kiezen', based on the American programme 'Choosing wisely', aims to improve quality in healthcare, with attention to cost control. The 'Choosing wisely'-based programme can be applied in the choice of a statin. Atorvastatin and rosuvastatin are regarded as equal choices in various guidelines regarding cardiovascular risk management. Generic atorvastatin is available, and is approximately 25 times cheaper than rosuvastatin in almost equipotent doses. Rosuvastatin provides a greater LDL reduction than atorvastatin. Patient LDL targets can usually be achieved with atorvastatin, and rosuvastatin is not needed. At group level, there are no relevant differences in adverse-events profile between both statins. Atorvastatin and rosuvastatin do have different pharmacokinetic interactions. When changing medication, good provision of information is a prerequisite for patient satisfaction and compliance. We advise use of atorvastatin instead of rosuvastatin as drug of choice when the LDL target is not reached using simvastatin. However, under specific conditions, rosuvastatin should be the treatment of choice. Efficacy and adverse effects should then be evaluated at individual patient level.

Diagnostic challenges of respiratory adverse events during everolimus treatment.

Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, non-everolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.