81 research outputs found
Multimodality treatment in hormone-refractory prostate cancer patients with bone metastases
We agree with the interesting points made by Koutsikos et
al. They confirm the feasibility of the combined use of
bone-seeking radiopharmaceuticals and bisphosphonates
and highlight the potential benefit of this combined
treatment. We would like to stress the importance to study
multimodality treatment strategies in well-designed clinical
trials. These trials should evaluate the multidimensional
character of pain, as well as survival, and they should
incorporate imaging modalities for response stratification ..
Four-year update of the EXIST-2 study
Objectives We examined the long-term effects of everolimus in patients with
renal angiomyolipoma associated with tuberous sclerosis complex or sporadic
lymphangioleiomyomatosis. Methods Following favorable results from the double-
blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive
open-label everolimus (extension phase). Patients initially randomly assigned
to everolimus continued on the same dose; those who were receiving placebo
crossed over to everolimus 10 mg/day. Dose modifications were based on
tolerability. The primary end point was angiomyolipoma response rate, defined
as a ≥50% reduction from baseline in the sum volume of target renal
angiomyolipomas in the absence of new target angiomyolipomas, kidney volume
increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The
key secondary end point was safety. Results Of the 112 patients who received
≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma
response. Almost all patients (97%) experienced reduction in renal lesion
volumes at some point during the study period. Median duration of everolimus
exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma
progression at some point in the study. No angiomyolipoma-related bleeding or
nephrectomies were reported. One patient on everolimus underwent embolization
for worsening right flank pain. Subependymal giant cell astrocytoma lesion
response was achieved in 48% of patients and skin lesion response in 68% of
patients. The most common adverse events suspected to be treatment-related
were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous
stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew
because of an adverse event. Renal function remained stable, and the frequency
of emergent adverse events generally decreased over time. Conclusions
Everolimus treatment remained safe and effective over approximately 4 years.
The overall risk/benefit assessment supports the use of everolimus as a viable
treatment option for angiomyolipoma associated with tuberous sclerosis complex
or sporadic lymphangioleiomyomatosis. Trial registration ClinicalTrials.gov
NCT0079040
Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases
Purpose: 153Sm-ethylenediaminetetramethylenephosphonic
acid (EDTMP; Quadramet®) is indicated for the treatment of
painful bone metastases, whereas zoledronic acid (Zometa®)
is indicated for the prevention of skeletal complications.
Because of the different therapeutic effects, combining the
treatments may be beneficial. Both, however, accumulate in
areas with increased osteoblastic activity. Possible drug
interactions were investigated.
Methods: Patients with hormone-refractory prostate cancer
were treated with 18.5 MBq/kg 153Sm-EDTMP in weeks 1
and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg
zoledronic acid began in week 3 and continued every
4 weeks through week 23. In weeks 3 and 15, zoledronic
acid was administered 2 days before 153Sm-EDTMP
treatment. Urine was collected 48 h after injection of
153Sm-EDTMP, and whole-body images were obtained 6,
24 and 48 h post-injection. The effect of zoledronic acid on
total bone uptake of 153Sm-EDTMP was measured indirectly
by the cumulative activity excreted in the urine in weeks 1, 3
and 15. Biodistribution, safety, tolerability and effect on
prostate-specific antigen level were also studied.
Results: The urinary excretion in week 3 divided by the
urinary excretion in week 1 (baseline) times 100% was
mean 98.4±11.6% (median 96.2%). From week 1 to 15,
after four zoledronic acid treatments, the mean ratio was
101.9±10.7% (median 101.8%). Bioequivalence could be
concluded by using a two-sample t test for both perprotocol
(n=13) and full-analysis sets (n=18). Toxicity was
comparable to of monotherapy with 153Sm-EDTMP.
Conclusion: Zoledronic acid treatment does not influence
153Sm-EDTMP skeletal uptake. Combined treatment is
feasible and safe
The TOSCA Registry for Tuberous Sclerosis-Lessons Learnt for Future Registry Development in Rare and Complex Diseases.
Introduction: The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to provide insights into the clinical characteristics of patients with Tuberous Sclerosis Complex (TSC). The aims of this study were to identify issues that arose during the design, execution, and publication phases of TOSCA, and to reflect on lessons learnt that may guide future registries in rare and complex diseases. Methods: A questionnaire was designed to identify the strengths, weaknesses, and issues that arose at any stage of development and implementation of the TOSCA registry. The questionnaire contained 225 questions distributed in 7 sections (identification of issues during registry planning, during the operation of the registry, during data analysis, during the publication of the results, other issues, assessment of lessons learnt, and additional comments), and was sent by e-mail to 511 people involved in the registry, including 28 members of the Scientific Advisory Board (SAB), 162 principal investigators (PIs), and 321 employees of the sponsor belonging to the medical department or that were clinical research associate (CRA). Questionnaires received within the 2 months from the initial mailing were included in the analysis. Results: A total of 53 (10.4%) questionnaires were received (64.3% for SAB members, 12.3% for PIs and 4.7% for employees of the sponsor), and the overall completeness rate for closed questions was 87.6%. The most common issues identified were the limited duration of the registry (38%) and issues related to handling of missing data (32%). In addition, 25% of the respondents commented that biases might have compromised the validity of the results. More than 80% of the respondents reported that the registry improved the knowledge on the natural history and manifestations of TSC, increased disease awareness and helped to identify relevant information for clinical research in TSC. Conclusions: This analysis shows the importance of registries as a powerful tool to increase disease awareness, to produce real-world evidence, and to generate questions for future research. However, there is a need to implement strategies to ensure patient retention and long-term sustainability of patient registries, to improve data quality, and to reduce biases
Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial
<p>Abstract</p> <p>Background</p> <p>Intra-arterial radioembolization with yttrium-90 microspheres ( <sup>90</sup>Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( <sup>166</sup>Ho-PLLA-MS) have been developed as a possible alternative to <sup>90</sup>Y-RE. Next to high-energy beta-radiation, <sup>166</sup>Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of <sup>166</sup>Ho-PLLA-MS radioembolization ( <sup>166</sup>Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of <sup>166</sup>Ho-RE in patients with liver metastases.</p> <p>Methods</p> <p>The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( <sup>99m</sup>Tc-MAA) dose, a low radioactive safety dose of 60-mg <sup>166</sup>Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of <sup>166</sup>Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the <sup>166</sup>Ho-PLLA-MS safety dose and the <sup>99m</sup>Tc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.</p> <p>Discussion</p> <p>This will be the first clinical study on <sup>166</sup>Ho-RE. Based on preclinical studies, it is expected that <sup>166</sup>Ho-RE has a safety and toxicity profile comparable to that of <sup>90</sup>Y-RE. The biochemical and radionuclide characteristics of <sup>166</sup>Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT01031784</p
Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis
Introduction The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. Methods For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). Results Of the 112 patients who received >= 1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm 3) from baseline was -70.56 (-88.30;-49.64) at time of everolimus discontinuation (n = 11), and -50.55 (-79.40;-23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. Conclusions Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth
Newly Diagnosed and Growing Subependymal Giant Cell Astrocytoma in Adults With Tuberous Sclerosis Complex: Results From the International TOSCA Study.
The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2
Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study
Objectives We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Methods Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose;those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a >= 50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade >= 2. The key secondary end point was safety. Results Of the 112 patients who received >= 1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time. Conclusions Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis
Treatment Patterns and Use of Resources in Patients With Tuberous Sclerosis Complex: Insights From the TOSCA Registry.
Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC
- …