Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT00185029 |
| Other study ID # |
sinerem1 |
| Secondary ID |
945-02-051 |
| Status |
Active, not recruiting |
| Phase |
Phase 4
|
| First received |
September 13, 2005 |
| Last updated |
September 14, 2005 |
| Start date |
April 2002 |
| Est. completion date |
August 2005 |
Study information
| Verified date |
September 2005 |
| Source |
Radboud University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
| Study type |
Interventional
|
Clinical Trial Summary
This proposal is targeted at all patients with prostate cancer who are candidates for either
curative surgery or curative radiotherapy in whom lymph node staging is indicated. Recently,
it has been shown, that in patients with PSA <10 ng/ml and Gleason score < 7 the risk of
lymph node metastases is low. Therefore, unnecessary PLND and non-invasive imaging can be
avoided safely in this group. PLND is nowadays performed only in patients with intermediate
or high risk for nodal metastases. Thus the subgroup of patients targeted in this study
consists of patients with prostate cancer with a PSA >10 ng/ml and Gleason score > 6.
- If the high sensitivity (90%) and negative predictive value (96%) of MRL can be
validated in the 8 participating centres, in patients with a negative MRL invasive PLND
may be avoided.
- In patients with a positive MRL with enlarged nodes (larger than 8 mm) histological
diagnosis may be obtained by imaged guided biopsy, and thus also in these patients
avoid PLND. A limitation of image guide biopsy, however, is the 30% false negative
rate. [Barentsz, Oyen, Wolf]
- In patients with positive small nodes (smaller than 8 mm) the urologist may, focussed
by the MRL findings of a positive node outside his “surgical field-of-view”, extend his
dissection, and thus improve his accuracy.
- Based on the expected higher sensitivity of MRL this technique will completely replace
CT-scanning.
Description:
Objective(s) of the proposed study The first objective of this study is to evaluate whether
MRL can replace currently used nodal staging techniques such as CT-scanning and PLND in
patients with prostate cancer. The second objective is to determine the effects of
implementing this new technique on diagnostic costs and the costs of therapeutic
consequences. The third, methodological, objective is to develop a protocol for diagnostic
test evaluation.
Define research questions of the proposed study
1. Can the results -especially the high sensitivity (92%) and high negative predictive
value (96%)- of a pilot study with a new nodal staging technique (MRL), be reproduced
by other investigators?
2. Can MRL improve the detection rate of small nodal metastases in normal sized nodes in
patients with prostate cancer, compared to CT and lymph node dissection?
3. Should MRL replace CT and PLND in the future, based on its high negative predictive
value?
4. Will replacement result in a decrease of the diagnostic costs and the costs of
therapeutic consequences with equal quality of life using a time horizon of 6 months?
Study design (motivate) The design of the study to compare MRL versus CT and PLND to detect
pelvic lymph node metastases in prostate cancer patients exists of two parts.
First to study the accuracy of the diagnostic options, consecutive patients will be
subjected to both MRL and CT and further diagnostic and therapeutic action will depend on
the absence or presence of lymph node metastases, irrespective of the test which indicated
the metastases. Given the fact that both tests are performed in every participating patient
and that both investigations will be made separately and read independently, a (randomised)
comparative study is not needed. Because negative MRL will lead to PLND (based on pilot in
72% of the cases) and a positive MRL (28%) to biopsy, this observational study makes it
possible to compare the MRL and CT results of all patients to the gold standard
(histological findings). In the patients who will undergo PLND, the results of PLND can be
compared directly to those of CT and MRL. As the imaging findings will guide the PLND, in
these patients also the additional value of the diagnostic imaging techniques, e.g. removal
of extra -image positive- nodes will be evaluated.
The second part of the study concerns the analysis of the economic aspects of both imaging
strategies in combination with further diagnostic and therapeutic courses of action. The
design for studying this aspect will be a decision analytic model. The first step in the
decision analysis is the design of the structure of the model. The model will reflect the
current clinical strategies compared to the alternative clinical strategy based on MRL. This
step of the decision analysis will exist of reviewing the literature in order to be able to
design a concept model structure. A meeting of radiologists and urologists of the
participating hospitals will be organised in order to discuss and validate the model
structure. The next phase in the modelling study will be the application of probabilities,
costs and patient outcome data in the model. The empirical part of the study will provide
the necessary data.
Selection criteria for study population / data sources / search strategy All patients with a
histologically proven prostate cancer who are scheduled for PLND are eligible for the study.
Patients are only included if they are at intermediate or high risk for lymph node
metastases (PSA > 10 ng/ml, and Gleason score > 6). Excluded will be patients below 18 years
of age, patients with contraindications for MRI (such as claustrophobia, pacemaker, surgical
clips in the brain), and patients with a history of severe allergy to contrast agents or
drugs (anaphylactic shock, severe asthma attack).
Description of the intervention(s) (including follow-up) / selection of information / data
extraction In 396 consenting consecutive patients with prostate cancer, meeting the study
criteria, a standardized diagnostic protocol is performed. The protocol includes both
standard CT and PLND as well as the new MRL technique.
CT scanning will be performed with state-of-the-art helical CT scanners using a slice
thickness of maximal 5 mm, with contiguous slices, after admission of intravenous and oral
contrast. On the CT scan lymph nodes will be rated positive based on size and shape
criteria, described by Jager et al.[Jager96] The MR-examination will be performed using
state-of-the art equipment (that is at a magnetic field strength 1.5 or 1.0 T using a body
phased-array coil) and sequences. Twenty-four to 36 hours after intravenous infusion of
USPIO (particle size 35 nm; Sinerem, Guerbet, Paris, France) at a dose of 2.6 mg Fe/kg MR
images will be acquired using high resolution 3 dimensional T1-weighted GRE, and 2
dimensional T2*-weighted GRE sequences. The T2*-weighted will be acquired in the axial and
“obturator” planes. The 3D sequences will be evaluated by soft-copy reading using
multiplanar reconstruction at a work-station. On the MRL images a node will be considered
benign if it shows a reduction in signal intensity involving the entire node on the
T2*-weighted MR images, otherwise it will be considered metastatic.
The CT and MR images will be assessed independently by two on-site readers and two
centralized readers. The CT readers are not aware of each others results, and of the MR
findings and vice versa. Prior to the start of the study the MRI protocol will be
implemented and the image quality will be tested by the principal investigator. During the
study regular quality control of both CT and MRL images will be performed, to ensure optimal
results. Before entering patients, a learning course will be organized by the principal
investigator to optimize the interpretation of the MRL images. For this purpose a set of
images from the pilot study showing normal and abnormal nodes will be used. Both CT and MRL
results will be used for further evaluation and treatment. If a positive enlarged node is
found, image guided FNAB will be attempted. If metastases are confirmed no PLND will be
done. When either CT or MRL show a small positive (< 10 mm) node, the patient will have an
image guided PLND. If CT and MRL are negative also PLND will follow. In case a metastasis is
proven with either FNAB biopsy or histopathologic examination after PLND the patient will
have hormonal therapy instead of prostatectomy or radiotherapy. If the nodes are negative
patients will undergo either prostatectomy or radiotherapy.
The PLND consists of either an open or a laparoscopic resection in which the obturator lymph
nodes, external iliac and hypogastric nodes on both sides are resected. The imaging results
are known prior to surgery by the urologist. He will be given a schematic drawing on which
the radiologist will indicate all visible nodes of the MR images in relation to the iliac
vessels, specifying both normal and suspicious ones. The urologist will be asked to dissect
both normal-appearing lymph nodes and those that appear enlarged, with specific attention to
pathological nodes on the CT and MR images. Also he will be asked whether the resected nodes
are within or outside his “surgical field of view”. During surgery the resected nodes will
be placed on a grid which shows its location, which will thereafter be sent to the
department of Pathology for further evaluation. The pathologist will indicate normal and
metastatic nodes on an identical drawing to the one provided to the urologist. The
histopathological examination of the nodes includes staining with hematoxylin and eosin, and
if possible Prostate Specific Antigen (PSA) staining.
Results of accuracy, sensitivity, specificity, negative and positive predictive value will
be calculated for the different techniques. Because lymph node tissue will be available from
all patients in the study, either by biopsy, laparoscopic or laparotomic PLND, histologic
examination will be considered the gold standard for the presence or absence of metastases.
Finally, end measurements (see below) will be performed and costs will be calculated. Also
an attempt will be made to select a sub-group of patients, based on pre-imaging information,
in which imaging is not cost-effective.
Primary and secondary outcome parameters (theoretical and operational) Primary outcome
parameters concern accuracy figures of both MRL and CT, being sensitivity, specificity, and
positive and negative predictive values of both diagnostic tests. Secondary outcome measures
are the costs per patient for each strategy. Besides this, quality of life after 6 months of
follow up will be part of the analysis in order to explore the idea that both diagnostic and
therapeutic strategies result in a comparable outcome at the patient level.
Sample size calculation (motivate assumptions) and feasibility of recruitment Based on the
pilot study in the prostate cancer patients (see above) the sensitivity of MRL is expected
to be 90% with a NPV of 96%. The percentage of patients with positive nodes is expected to
be 26%. In this study we intend to assess the accuracy of the new diagnostic test (MRL). We
specifically do not intend to assess a statistically significant difference between the
diagnostic performance of CT and MRL. The reason for this is that we believe that such a
statistically significant difference per se is of no clinical relevance. It is merely the
diagnostic performance of MRL itself which is the key factor whether the test will be
implemented into clinical practice or not. The power analyses was therefore based on the
reliability of the validity estimates. Following the paper by Buderer [Buderer] we evaluated
the sample size needed to obtain a width of 6% of the 95% confidence interval around the
sensitivity and specificity. With the expected sensitivity, specificity and prevalence of
patients with positive nodes 376 patients are needed for the study to assess the reliability
of the new diagnostic test (MRL) independent of the other test. Given a percentage of 5%
lost to follow up 396 patients will be included in the study.
Data analysis and presentation / synthesis The CT, MRL and PLND will be performed and
interpreted in a standardised way (see “description of intervention”). The evaluation of the
image findings will be performed independently by 2 on-site readers and 2 centralized
readers. To test the reproducibility, the degree of agreement between observers will be
quantified with kappa statistics. The diagnostic accuracy sensitivity, specificity, negative
predictive and positive predictive value of pre- CT and MRL will be determined in relation
to PLND and histopathologic findings with 95% confidence interval. Statistical analysis will
be carried out with SAS software. The additional nodes found by PLND based on the image
findings will be recorded.
The decision analytic model will indicate the probability that a prostate cancer patient is
diagnosed correctly regarding lymph node metastases. The expected costs of both strategies,
the one with MRL and the one without, will be calculated by combining probabilities of
clinical events happening and the costs involved. Multi-variable uncertainty of the data
used in the model will be explored using probabilistic sensitivity analysis. The
distributions of the variables to be used in this uncertainty analysis will reflect the
uncertainty of these variables as found in the empirical study. For probabilities used, a
confidence interval will be determined and for the variables indicating costs the range of
cost prices found in the participating hospitals will be basis for this probabilistic
sensitivity analysis. In this way, the uncertainty of the difference in cost of both
strategies can be determined. In case one of the strategies will be both more expensive and
more effective in terms of patient outcome, an incremental cost-effectiveness ratio such as
the additional diagnostic costs per extra patient diagnosed correctly will be calculated.
The uncertainty surrounding this ratio will be presented in a cost-effectiveness
acceptability curve. In a one way sensitivity analysis the important accuracy data much as
the false positive rate and the false negative rate of MRL will be varied in order to study
the impact of possible efficacy modifying after implementation of MRL from this clinical
study in day to day health care practise. The impact of these parameters on the modelling
results will be indicated by adjusting the cost-effectiveness acceptability curve.
Economic evaluation: general considerations The economic evaluation will concentrate on the
comparison of the two diagnostic strategies in combination with the therapeutic follow up to
determine the presence or absence of pelvic lymph node metastases in prostate cancer
patients either by MRL or CT in combination with PLND. The empirical study is a
non-comparative observational study, therefore the economic evaluation will be based on a
decision analytic model using the data from the observational study comparing two possible
diagnostic strategies: MRL versus CT and PLND. The general considerations motivating the
design of the economic evaluation are the following: although MRL compared to CT in
combination with PLND is expected to lead to a more accurate and therefore more adequate
treatment of the patient having prostate carcinoma, the patient outcome for the longer term
is not expected to be different between the strategies. Therefore, the economic evaluation
is based on the principles of a cost minimisation analysis. Using a differential approach
patients are followed up for a period of 6 months because this period will cover the
expected and most important differences in diagnostic and therapeutic care and thus the
direct medical costs. Because of the specific patient population in this study non medical
costs are not expected to be different between the patients groups, thus a health care
perspective is basis for the analyses, indicating that only health care costs are subject to
study. The research question of the economic evaluation is: will this result in a decrease
-and how much- of the diagnostic costs and the costs of therapeutic consequences with equal
quality of life using a time horizon of 6 months?
Economic evaluation: cost analysis In the decision analytic model MRL or CT in combination
with PLND will lead to different therapeutic courses of action. The cost analysis reflecting
these courses of action will be based on the empirical data gathering. The cost analysis
exists of two main parts. First, on the patient level volumes of diagnostic and therapeutic
care will be measured prospectively using standardised Case Report Forms (CRF). In each
participating hospital research nurses will register in the CRF the number of times a
patient visits the out patient department, the number of days in hospital (normal care and
intensive care distinguished), the number and kind of diagnostic procedures (MRL, CT,
histological examination), the type and number of operations (biopsy, laparoscopic lymph
node dissection, laparotomic lymph node dissection, the latter in combination with radical
prostatectomy), the duration of the specific operations, the number and duration of
radiotherapeutic sessions, the personnel involved, the amount and kind of pharmaceutical
therapies (e.g. hormonal therapy, pain killers) and so on. An important aspect in the cost
analysis as input for the decision analytic model is the cost related to the false positives
and false negatives regarding MRL and CT in combination with PLND. This part of the CRF will
be designed and pilot tested in the first months of the study. The second part of the cost
analysis consists of determining the cost prices for each volume parameter to use these for
multiplying the volumes registered for each participating patient. The Dutch guidelines for
conducting pharmaco-economic studies. [CVZ] and the guidelines for cost analyses will be
used.[Oostenbrink] Because of the health care perspective of the study, approximations of
real integral costs will be used in the cost analysis. As a basis for the cost price
calculations in each participating hospital based on standardised calculation methods a
costing study will be performed resulting in several estimates of a cost price. For the
baseline analysis a weighed average (using the number of patients included in the study by
each participating hospital) will be used. The range of the resulting cost prices and, if
available, the reference values as mentioned in the national guidelines for each volume item
will be used in extensive sensitivity analyses.
Economic evaluation: patient outcome analysis As a main outcome of the observational study,
several parameters for the accuracy of MRL versus CT in combination with PLND will be
determined. Although no difference is expected in final patient outcome (survival), correct
and incorrect diagnosis of the pelvic lymph node status of the patient may lead to different
short term effects on patient outcome. To explore these possible differences quality of life
measurement is foreseen in the observational study. A description of the disease specific
and generic quality of life of the prostate cancer patient will be given on the basis of the
intake measurement using the UCLA prostate cancer index and MOS short form 36 (SF36),
respectively. The UCLA Prostate Cancer Index can be used for men with prostate cancer and
can be administered in about 20 minutes. It includes six disease-specific domains to measure
function and dysfunction in urinary, sexual, and bowel domains. The SF36 studies the domains
physical functioning, problems with role functioning due to emotional problems, pain, mental
health, vitality, and general health perception. It reports each domain in a figure between
0 and 100 without generating a general score, however. This instrument is applied in a wide
variation of patient populations and is considered to be reliable, valid, and sensitive. At
the end of the follow up (6 months after intake), the same set of questionnaires will be
completed by the participating patients. Analysis of these data will concentrate on
exploring a possible difference in change of quality of life form intake to end of follow up
between patients in whom the status of the pelvic lymph node metastases (present or absent)
was diagnosed correctly immediately or missed initially. In case a difference does exist
contrary to our expectations, these patient outcomes will be used in the decision analytic
model and will lead to a cost-effectiveness analysis instead of a cost-minimization
analysis.
Time schedule Include information about the organisation and planning The study period is 3
years. In the first 3 months (month 1-3) the diagnostic protocols will be optimized, with
monthly joined meetings of all participating centers. During the following inclusion period
(month 4 to 29), data will be collected and plenary meetings once every 3 months will take
place or more frequently if needed. Co-ordination between centres is further facilitated by
initially weekly and later in the study monthly meetings of the principal investigator and
research personnel (research fellows, research nurses, administrative personnel). In this
period 396 consecutive consenting patients will be included, and the outcome of the
diagnostic tests is evaluated after 3, 12 and 20 months (respectively month 7, 16 and 24).
Inter and intra-observer variation studies are also performed in this period.
All patients will complete the study within 29 months. Data will be collected at the
participating hospitals in a uniform way (CRF) and sent to the UMC Nijmegen. In the final
period (month 29-35) the analysis of the economic aspects (modelling study) will be
performed by the Department of Medical Technology Assessment at the UMC Nijmegen. In the
final month study findings will be reported and practice guidelines will be presented.
An interim analysis of the results of CT and MRL (sensitivity, specificity, NPV. PPV ,
accuracy) will be performed after 150 patients. As the negative predictive value of MRL
should be at least 90%. The NPV is expressed by the formula:
NPV= spec (1-prevalence) spec (1-prevalence) + prevalence (1-sens) Especially the
sensitivity and NPV of MRL are critical. Assuming a fixed specificity of 93% and a fixed
prevalence of positive nodes of 26%, the sensitivity should at least be 70% to obtain a
negative predictive value of 90%. The study will be stopped if the sensitivity is
statistically significantly smaller than 70%. Assuming a binomial distribution the cut-off
points for the sensitivity at n=150 is 62%. For the NPV the cut-off value which is
significantly lower than 90% is 83.5%.
Although a low specificity will not result in different diagnostic results and there will
not be increased costs, the study will be stopped if the specificity is lower than 75% after
150 patients, because a lower specificity will have a negative effect on the acceptance (and
thus implementation) of MRL.
