Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02229916 |
| Other study ID # |
SG359/13 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 2013 |
| Est. completion date |
December 2033 |
Study information
| Verified date |
August 2023 |
| Source |
Cantonal Hospital of St. Gallen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
The majority of testicular cancer patients can be cured with cisplatin-based chemotherapy.
Mortality has been reduced even more within the last 15 years due to the stringent
application of standard chemotherapy followed by resection of residual disease. This is a
positive development considering that testicular cancer usually affects young men. Active
surveillance has become an acceptable and widely used strategy in stage I testicular cancer.
Thus, it is important to follow these patients in a standardized way and to adhere to a
rationale surveillance strategy. There is no international consensus regarding follow-up of
testicular cancer patients. Stratification according to risks and patterns of relapse would
allow to tailor follow-up schedules, aiming at early identification of relapse without
causing unnecessary harm by using excessive radiation in these young long-term survivors.
Follow-up procedures should not only aim at detecting relapse, but also long-term side
effects from therapy, including hypogonadism, metabolic syndrome, cardiovascular disease and
secondary malignancies. The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS)
will comprise consecutive newly diagnosed testicular cancer patients and is the first study
to prospectively evaluate the initial indictor of relapse in testicular cancer patients, the
frequency and pattern of relapse and document long-term toxicities of the treatment
(cardiovascular, gonadal, hearing impairment, renal function and second malignancies) and
psychosocial aspects. This cohort study will determine the relevance of each test performed
routinely during follow-up. The collected data will have direct implications for the care of
patients with testicular cancer and inform future adaptations of follow-up recommendations.
The dataset will give information on baseline factors of testicular cancer patients patients,
current treatment strategies in Switzerland, Austria and Germany, outcome and late sequelae.
Description:
Objectives
Primary objective
The primary objective is to determine the diagnostic performance and the clinical impact of a
variety of tests, including conventional radiographs, computer tomographies (CT), abdominal
ultrasound, serum tumour markers (AFP, beta-HCG and LDH) and clinical signs and symptoms
aimed at early detection of relapse after curative therapy with documented complete
remission.
Secondary objectives
Diagnostic performance:
1. To determine the rate of relapses detected on chest x-ray in seminoma patients.
2. To determine the rate of false positive abnormalities on CT scan and of false positive
tumour marker elevations not due to seminomatous or non-seminomatous germ cell tumour
relapses but due to other processes.
3. To determine the modality to rule out testicular cancer relapse in patients with false
positive index tests.
Pattern of care:
4. To assess patient characteristics at baseline and at the time-point of relapse
detection.
5. To determine the rate of stage I seminoma and non-seminoma patients undergoing active
surveillance.
6. To obtain an overview of treatment and follow-up strategies in germ cell cancer patients
in Switzerland.
Outcome:
7. To collect data on treatment sequelae following testicular cancer treatment in terms of
organ function, cardiovascular risk factors, sexual health and socioeconomic aspects.
8. To determine the rate of intermediate and poor-prognosis disease at relapse.
9. To determine the rate of offspring spontaneously conceived after testicular cancer
treatment.
Design
Prospective cohort study
Centres All urologists, radiooncologists and oncologists are motivated to enrol their
patients. We will aim at enrolling the majority of patients treated and followed in private
practice.
Patients Consecutive patients with testicular cancer of any type and any stage (incident
cases). Testicular cancers are generally classified as seminomatous (seminoma) and
nonseminomatous germ cell tumours (non-seminoma) of the testis. Mixed germ cell tumours
belong to the group of non-seminomas. The stage of disease and the choice of treatment
(active surveillance vs. chemotherapy vs. radiotherapy) define the risk of relapse, the
pattern of relapse and the long-term toxicities. Staging in testicular cancer is performed
according to the American Joint Committee on Cancer (AJCC) primary tumor, regional nodes,
metastasis (TNM) staging system for testis cancer. Metastatic testicular cancers are
classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk
groups.
Clinical outcome
Relapse of testicular cancer will be defined as rising concentrations of serum
alphafetoprotein (AFP) above the upper limit of normal (typically > 13 μg/l) and/or human
chorionic gonadotropin (HCG) above the upper limit of normal (typically > 5 U/l) and/or
lactate dehydrogenase (LDH) above the upper limit of normal and confirmation of this rise in
a second test four weeks later and/or radiographic evidence of metastatic disease in typical
locations, and/or the presence of active germ cell tumour established by biopsy, whatever
comes first.
Index tests
The following tests will be performed (ordered according to their burden for patients and
cost): symptom assessment, physical examination, tumour marker measurement, chest x-ray,
abdominal ultrasound and CT scan of abdomen and pelvis.
Procedures
Follow-up will be performed according to the mandatory follow-up schedule by a physician who
has substantial experience in the treatment and surveillance of patients with germ cell
tumours. Follow-up comprises thorough assessment of medical history and patients' symptoms
with a focus on pain, appetite, fatigue, sexual function and activities of daily living;
physical examination includes lung auscultation, abdominal, axillary, supra- and
infradiaphragmatic regional lymph nodes and testicular palpation; serum tumour marker
measurement: AFP, HCG and LDH; chest x-ray and abdominal ultrasound or CT scan. Even though
the role of LDH in the follow-up is debatable, due to limited sensitivity and specificity and
a high rate of false-positive tests, it can contribute to identify relapse in a significant
number of cases, as shown in a recent publication. All the laboratory and radiological tests
are performed independently and results are not made available to the investigator prior to
symptom assessment and physical examination. In addition we will ascertain cardiovascular
risk factors (smoking status, lipid profile, bodymass index, fasting glucose etc.), renal
function, testosterone level, follicle stimulating hormone (FSH) level, lutenizing hormone
(LH) level, and socioeconomic characteristics (education, employment, partnership) in annual
intervals.
Statistics
Sample size considerations
There are approximately 400 newly diagnosed testicular cancer patients in Switzerland per
year. In Germany the annual testicular cancer incidence is about 4000. We aim at including
approximately 300 patients per year in Switzerland over a duration of 3 years, with a total
number of 900 patients. We are also aiming at registration of 2000 patients per year in
Germany. Looking at the Swiss cohort, with an estimated 15% rate of relapses over a follow-up
duration of two years, this will yield approximately 135 cases with relapse. This number will
yield satisfactory statistical precision. An assumed sensitivity of 50% and a specificity of
95% for Beta-HCG, for example, to detect a relapse will yield a positive likelihood ratio
(LR) of 10 and a negative likelihood ratio of 0.53. Corresponding 95% confidence intervals
will be 42 to 58% for sensitivity, 93 to 97% for specificity, 7.0 to 14.2 for the positive
likelihood ratio and 0.44 to 0.62 for the negative likelihood ratio. An assumed sensitivity
of 37% and a specificity of 99% for CT scans, for example, to detect a relapse will yield a
positive likelihood ratio of 37 and a negative likelihood ratio of 0.64. Corresponding 95%
confidence intervals will be 29 to 45% for sensitivity, 98 to 100% for specificity, 17.7 to
77.4 for the positive likelihood ratio and 0.56 to 0.72 for the negative likelihood ratio.
Measures of diagnostic accuracy will be determined in relation to the occurrence and
timepoint of diagnosis of a relapse as specified above. Tests that were positive within the
previous 8 weeks of established diagnosis of relapse will be considered as true positives,
tests that remained negative during this time period as false negatives. Conversely, tests
that were positive before this time period will be considered as false positives, and tests
that were negative before this period as true negatives. We will use a multi-level model with
random effects at the level of patients and time-points to estimate sensitivities and
specificities and likelihood ratios, with the data organised in long format, with each test
outcome (positive or negative) at each time-point represented by one line in the dataset,
determining for each time-point whether it is within the 8-week time-period previous to the
time-point of established diagnosis of relapse. The model takes into account the correlation
of multiple time-points and tests within patients. The positive LR indicates how much more
likely it is to find a positive test in patients with a relapse (sensitivity) as compared
with those without relapse (1-specificity). Conversely, the negative LR specifies how much
less likely it is to find a negative test in patients with relapse (1-sensitivity) as
compared to patients without (specificity). A test will be considered to provide clinically
relevant power to rule in or out a relapse if the positive and negative LRs are above 5 or
below 0.2, respectively. The test will be considered to have a strong power to rule in or out
a relapse if LRs are above 10 or below 0.1, respectively.
As measures of the clinical impact of the addition of more extensive tests, we will examine
the net re-classification improvement and the integrated discrimination improvement. The net
re-classification improvement through the addition of a more extensive test is defined as the
improvement of the probability of the appropriate classification of patients according to
relapse status (presence or absence of a relapse), which is afforded by the addition of the
more extensive test. This corresponds to the sum of differences in proportions of individuals
classified positive minus the proportion classified negative for individuals who develop
events, and the proportion of individuals classified negative minus the proportion classified
positive for individuals who do not develop events. The integrated discrimination improvement
is defined as the improvement in average sensitivity afforded by the addition of the more
extensive test minus the potential loss in specificity afforded by the addition of the more
extensive test. All analyses will be done using Stata, Release 11 (Stata Corp LP, College
Station, TX).
