This study has been transitioned to CTIS with ID 2024-514919-10-00 check the CTIS register for the current data. To investigate if the use of weekly low dose cisplatin increases compliance to the planned chemotherapy scheme in LA-HNSCC patients with…
ID
Source
Brief title
Condition
- Oral soft tissue conditions
- Miscellaneous and site unspecified neoplasms malignant and unspecified
- Head and neck therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome parameter is compliance (non CDLT) rate to the proposed
cisplatin scheme. Compliance to chemotherapy is defined as the absence of CDLT.
CDLT is defined as any toxicity resulting in a cisplatin dose-reduction of
>=50%, a postponement of treatment of >=4 days or a definite termination of
cisplatin after the first or second cycle of therapy.
Secondary outcome
Secondary outcome parameters are adverse events/toxicity, cumulative cisplatin
dose, time to recurrence, 2-year overall survival, costs, quality of life and
patient*s preference. The main oncological outcome parameters are time to
recurrence and survival. Clinically relevant treatment related toxicity
parameters, including specific toxicity that results in significant (grade 3 or
4) toxicity, treatment de-escalation or termination, will be recorded by the
treating medical oncologist. Toxicity will be scored according to the Common
Terminology Criteria for Adverse Events (CTCAE) guidelines, v5.0.
Questionnaires The following questionnaires will be used to measure quality of
life: EORTC QLQ-C30, EORTC-QLQH& N35 and EQ-5D-5L. Global quality of life is
assessed with the EORTC-QLQ-C30 global measure. The EORTC-QLQ-H&N35 is designed
to be head and neck cancer-specific, multidimensional in structure, appropriate
for self-administration and applicable across a range of cultural settings. The
EQ-5D-5L is a standardized instrument can be used as a quantitative measure of
health outcome that can be used in a wide range of health conditions and
treatments, and reflects the patient*s own judgement. Questionnaires are asked
to fill out before and 3, 6, 12 and 24 months after CRT. Standard scoring
methods are applied to quality-of-life questionnaires. All scores are
normalized, ranging from 0 to 100, and transformed to unweighted summated
scales in which higher scores indicates better health. Separate comparisons are
made at each time point. Unadjusted p values are used. On the EORTC
questionnaires a 10-point difference in scores was considered to be clinically
relevant. Cost analysis Substitution of weekly low dose cisplatin for
three-weekly high dose cisplatin in patients treated with concurrent CRT is
expected to result in cost-savings and an increase in quality of life due to
reducing the number of complications. A detailed analyses of cost differences
for low SMM patients with weekly low dose cisplatin and standard of care
(three-weekly high dose cisplatin) demands a detailed collection of all health
care consumed by these patients in relation to the intervention and
complications. In the prospective cohort we will collect all health care
consumed by patients in each of the three different groups with a follow-up of
12 months. All data will be collected from the electronic patient files in each
different hospital and will be collected using respective units for each sort
of health care consumption (hospital stay per day, cost per dose, etc). As
indicated, quality of life will be measured before and 3, 6, 12 and 24 months
after CRT using the EQ-5D-5L. Productivity loss of low SMM patients will be
collected during the study at baseline and at 12 months after CRT using the
productivity cost questionnaire (PCQ). This will only be done for the low SMM
group, since our main interest is the difference between the two chemotherapy
schemes in the low SMM group. All different units of care consumed will be
linked to their respective unit costs. Reimbursement prices issued by the Dutch
Healthcare Authority (NZA) and national reference prices will be used for this
assessment as outlined in current Dutch pharmaco-economic guidance. In addition
to total health care consumption of these patients it is essential to perform
micro-costing of CRT treatment to have detailed insight in the additional
costs. We therefore aim to perform a micro-costing study using the activity
based costing (ABC) method. To link both costs and effects we aim to develop a
decision-tree completely outlining all probabilities of having complications
(CDLT resulting in non-compliance) and their respective costs and effects
(quality of life) in each of the three different groups. Outcome measure will
be incremental costs per quality adjusted life year. Moreover, complete
sensitivity analysis (both deterministic as well as probabilistic) will be
carried out to have detailed insights into the impact of uncertainty on our
outcome measures. In addition to a cost-effectiveness analyses we aim to
perform a budget impact analysis (BIA) as well. The BIA adheres to the
Zorginstituut guidelines and applies the perspectives: societal, health
insurance/third party payer and health care (Budgetair Kader Zorg (BKZ)). The
BIA Prices will be linked to perspectives: societal-CEA based prices,
BKZ-average rates according to NZa, for health insurance perspective also NZa
average rates and, for example, for a local health care provider perspective
specific passenger rates (*passanten tarieven*). The BIA will be assessed
through (decision analytical) modelling and analyzed in a probabilistic way.
Other parameters: To allow for comparison with the recent nation-wide Dutch
Head and Neck Society audit, the same characteristics and potential predictive
factors will be scored. Collected patient characteristics are gender, age,
weight, stature (length), smoking history, use of alcohol, loss of weight,
Eastern Cooperative Oncology Group (ECOG performance status), medical history
regarding heart, lung, diabetes mellitus, oncology and nefrology, grip strength
(if available), comorbidity (ACE-27 and Charlson Comorbidity Index), Tumor Node
Metastasis (TNM) classification, tumor localisation, estimated Glomerular
Filtration Rate (eGFR), serum creatinine, neutrophil count, platelet count,
leukocyte count, lymphocyte count, monocyt count and hemaglobin level, baseline
audiometry results and treatment plan (including use of co-medication). SMM
will be estimated using a validated technique based on measurement of the
cross-sectional area of the sternocleidomastoid muscle and paravertebral
muscles on the level of C3 on routinely performed CT or MRI. In patients who
underwent fluorodeoxyglucose-positron emission tomography(FDG-PET)/CT as part
of the diagnostic work-up, as a control of SMM measurement at the level of C3,
SMM will also be measured at the level of L3, which is the most commonly used
method in medical literature as a control of SMM measurement at the level of
C3. Based on the cut-off value calculated by Wendrich et al., low SMM is
defined as skeletal muscle mass <43,3 cm2/m2. Patients with low SMM will be
randomised between weekly low dose cisplatin and three-weekly high dose
cisplatin with concurrent RT. The rate of compliance to proposed cisplatin
scheme will be compared between three groups: patients with low SMM with weekly
low dose cisplatin, patients with low SMM and three-weekly high dose cisplatin
and the rest group of normal SMM receiving standard three-weekly high dose
cisplatin.
Background summary
In the Netherlands, 3160 patients were diagnosed with HNSCC in 2018. Two-thirds
of HNSCC patients present with locally advanced disease (LA-HNSCC). The
standard of care consists of intravenous cisplatin concurrently given with
conventional external beam radiotherapy (chemoradiotherapy, CRT). High
cumulative cisplatin dose is associated with better outcome. The most commonly
used scheme is three-weekly high dose cisplatin of 100mg/m2. Though effective
in terms of overall survival (OS) and loco-regional control (LRC), high rates
of severe acute events lead to cisplatin dose limiting toxicity (CDLT) in up to
40% of patients and cause decrease in local control and survival. Furthermore
in 13% of the patients late toxicity is reported, which leads to permanent
comorbidity. This is a high rate of adverse events in comparison to other
anticancer treatments. Decresed compliance to treatment because of CDLT can
lead to a cumulative dosage less than the adviced >200 mg/m2, which leads to
worsened local control of disease and survival. Therefore another commonly used
scheme is weekly low dose cisplatin of 40 mg/m2 during 7 weeks concurrently
given with radiotherapy (RT). This scheme is considered as standard in daily
clinical care. However, the most scientific evidence is available for the
three-weekly scheme and for the whole patient population the weekly scheme does
not lead to improved survival. Currently, patients at risk for CDLT cannot be
accurately identified upfront and thus it is not possible yet to decide which
patients possibly benefit from the weekly scheme. However, it is known for
patients with low skeletal muscle mass (SMM), assessed on routinely performed
CT and/or MRI scans, are three times more likely to develop CDLT than patients
with normal SMM. Cisplatin possibly distributes mainly to the fat-free mass, of
which SMM is the largest component, and thereby a higher and more toxic peak
dosage might be reached in patients with low SMM receiving high dose cisplatin.
Since early discontinuation of therapy automatically leads to a reduced
cumulative cisplatin dose, which is associated with lower overall survival, it
can be anticipated that particularly patients with low SMM might benefit from
weekly low dose cisplatin based concurrent CRT to achieve a adequate cumulative
dose comparable to patients with normal SMM.
Study objective
This study has been transitioned to CTIS with ID 2024-514919-10-00 check the CTIS register for the current data.
To investigate if the use of weekly low dose cisplatin increases compliance to
the planned chemotherapy scheme in LA-HNSCC patients with low SMM to a level of
compliance to three-weekly high dose cisplatin of patients without low SMM. We
hypothesize that in LA-HNSCC patients with low SMM, receiving weekly low dose
cisplatin concurrent RT have a higher compliance rate to planned chemotherapy
scheme compared to patients receiving the three-weekly scheme, resulting in a
higher cumulative dosage and possibly improved outcomes.
Study design
In this multicenter prospective low-intervention clinical trial the compliance
of weekly low dose compared to three-weekly high dose cisplatin with concurrent
RT in seventy LA-HNSCC patients with low SMM will be investigated. To assure
the inclusion of seventy low SMM patients, a total of 160 LA-HNSCC patients
should be included according to the incidence rate of low SMM in this
population. The goal of this study is to treat patients more effective and
safer. Patients with low SMM will be randomised between two schemes, weekly low
dose cisplatin versus three-weekly high dose cisplatin. Both schemes are
considered as standard of care in which the goal is to obtain a equivalent
cumulative dosage.
Cumulative cisplatin dose, time to recurrence, 2-year overall survival, costs,
quality of life and patient*s preference will be assessed. Toxicities will be
recorderd using the Common Terminology Criteria for Adverse Events (CTCAE)
criteria. Quality of life will be measured using European Organisation for
Research and Treatment of Cancer (EORTC) questionnaires and will be send by
e-mail. When the patient or treating physician ask for a non-digital
questionnaire, the questionnaires will be send via post and answers will be put
into Castor by the investigator. A cost-effectiveness analysis will be
performed. Semi-structured interviews will be done, to assess patients'
preferences.
Intervention
Randomisation between high- (100 mg/m2 cisplatin three-weekly) and low dose (40
mg/m2 cisplatin weekly) treatment in patients with low SMM. Cisplatin treatment
itself and concomitant radiotherapy are not part of the intervention, but part
of standard treatment. The intervention is not cisplatin or radiotherapy
because those are both part of standard of care, but the intervention is the
randomisation between schemes. Patients with a normal SMM receive the scheme
that is the local standard of care.
Study burden and risks
Burden to patients is limited to completion of four (or three when the patient
has normal SMM) questionnaires for five times, which will take about 30 minutes
and a 10-minute interview over the phone with the investigator 3 months after
therapy. Therefore it is likely that most patients will agree to participate.
There will be no need for extra diagnostic procedures, because MRI and/or CT at
cervical level is standard pre-treatment procedure in LA-HNSCC.
Moreover each patient receives RT daily, so no additional hospital visit is
necessary: Radiotherapy will be given daily during 7 weeks. Chemotherapy will
be given three or seven times, depending on the randomisation group, on a day
radiotherapy is planned as well. For low SMM patients, this study may serve as
a basis for increase in compliance to therapy and might increase survival and
LRC, since early discontinuation of CRT increases risks at recurrence of
disease.
Heidelberglaan 100
Utrecht 3508GA
NL
Heidelberglaan 100
Utrecht 3508GA
NL
Listed location countries
Age
Inclusion criteria
- considered eligible and planned for primary cisplatin CRT by treating
physician;
- eighteen years of age or older;
- sufficient understanding of Dutch and medical consequences to give informed
consent.
Exclusion criteria
- mentally disabled or patients with significantly altered mental status that
would prohibit understanding and giving informed consent; - a history of
bilateral lymph node dissection in the neck and no available (PET-)CT scan of
the third lumbal vertebra; - an absolute contraindication for cisplatin as
defined by the treating physician, including relevant pre-existing kidney
insufficiency, clinically apparent vascular disease (for example claudicatio
intermittens), clinically relevant perceptive deafness, serious neuropathy and
poor performance score. - an absolute contraindication for high dose
three-weekly cisplatin 100 mg/m2 as defined by the treating physician; -
interval between diagnostic scan and planned CRT >2 months; - cisplatin CRT
planned as non-primary or induction treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514919-10-00 |
| EudraCT | EUCTR2021-002634-16-NL |
| CCMO | NL76533.041.21 |
| Other | NL9217 |
| OMON | NL-OMON25064 |