Cisplatin pharmacokinetics and skeletal muscle mass in patients with head and neck cancer: is cisplatin overdosed in patients with low skeletal muscle mass?

Introduction
Head and neck cancers (HNCs) are among the most frequent tumours in the world
with an estimated 529,510 new cases and 292,289 deaths in 2012. There has been
a significant increase in the global incidence of HNC over the past decade. In
the Netherlands, the incidence of HNC increased with 20% from 15.8 in 2004 to
18.2 per 100,000 person-years in 2014. More than 90% of all HNCs are head and
neck squamous cell carcinomas (HNSCC). Prolonged tobacco use and alcohol
consumption are the main risk factors associated with HNSCC. In increasing
numbers, a specific subset of HNSCC located in the oropharynx is caused by
human papillomaviruses (HPV), most specifically HPV 16 and 18. Generally, HPV
related HNSCC has a better prognosis. (5,6) Early stage HNSCC (T1-T2, N0, M0)
HNSCC is often curatively treated with surgery or radiotherapy alone.
Two-thirds of HNSCC patients present with advanced disease at diagnosis (large
tumor, regional metastasis and/or distant metastasis). Patients with advanced
stage HNSCC are often treated with primary radiotherapy combined with
concurrent platinum based chemotherapy (CRT; generally 70 Gray total radiation
dose combined with 3 cycles cisplatin), with salvage surgery reserved for
residual or recurrent disease. In patients treated between 2005 and 2011, the
5-year overall survival of HNSCC in the Netherlands was 58%. Despite improved
quality and organisation of care, survival of HNSCC has only slowly improved
over the past 10-15 years.

Due to the addition of platinum-based chemotherapy such as cisplatin to primary
radiation treatment in HNSCC, disease specific survival has improved with
approximately 8%. Primary CRT also offers the chance of organ preservation
(e.g. larynx) in advanced stage tumours, with roughly equal survival numbers
as primary surgery. However, the addition of cisplatin to radiation treatment
can cause severe side effects (e.g. mucositis, bone marrow depression,
ototoxicity or nephrotoxicity). It is currently difficult to predict which
patients are at risk of developing severe treatment related toxicity. Acute
toxicity is a common and serious problem in HNSCC, and may result in
dose-reductions, treatment delay or treatment termination (chemotherapy dose
limiting toxicity) in up to 30 percent of patients. It can be anticipated that
dose-limiting toxicity has a negative effect on the survival of HNSCC patients,
because patients end up receiving a suboptimal treatment. Indeed, in a recent
study conducted in the UMC Utrecht, patients with HNSCC who experienced CDLT
has a significantly lower overall survival compared to patients who did not
experience CDLT (35% versus 50%, p < 0.001). The treatment-related toxicity
itself can also have a negative effect on survival, both in short-term and
long-term. Lastly, the occurrence of significant toxicity has a negative effect
on quality of life.

Cisplatin, the chemotherapeutic agent most often used in HNSCC patients, is
commonly dosed according to a patient*s body surface area (BSA), which takes
into account a patient*s height and weight. Chemotherapy dosing using BSA is
based on the assumption that larger patients have a higher drug elimination
capability and need higher chemotherapy doses for optimal treatment. The
optimal chemotherapy dose for a patient is commonly defined as the highest
possible dose to be given to the patient with the occurrence of, at most,
acceptable toxicity. Currently, there is substantial unexplained
interindividual variation in a patients* tolerance of cisplatin and the
occurrence of toxic side effects. Previous research has shown that drug dosing
based on BSA poorly predicts plasma drug concentrations of most cytotoxic drugs
in individual patients, including cisplatin, possibly explaining the
interindividual variation of the occurrence of toxicity. However, a better
alternative to dosing based on BSA has not yet been formulated.

In the last decade, the body composition of cancer patients has been
investigated extensively using standard diagnostic CT imaging. The different
body compartments, such as skeletal muscle mass and adipose tissue mass, can be
accurately quantified using this method. Specifically a low skeletal muscle
mass, sometimes termed sarcopenia, has been related to negative outcomes in
variety of tumour types and treatments. Risk factors for low skeletal muscle
mass are, amongst others, old age, malnutrition, immobility and illness;
factors which are common in head and neck cancer patients. Another factor which
has been related to low skeletal muscle mass is an increased systemic
inflammation in cancer patients. The mechanisms leading to a substantial
decrease in skeletal muscle mass in cancer patients have not yet fully been
elucidated.

Commonly, for skeletal muscle mass assessment, the skeletal muscle area at the
level of the third lumbar vertebra (L3) is measured on a single CT slide. The
skeletal muscle area at the level of L3 has shown excellent correlation with
whole body skeletal muscle mass as measured with whole body MRI, which is
considered the golden standard. In head and neck cancer patients, abdominal
imaging is not routinely performed, but recent studies showed that skeletal
muscle mass also can accurately be assessed in HNSCC patients using diagnostic
CT imaging of the head and neck area.

Rationale
Recent retrospective studies in a variety of cancer types have shown an
association between low skeletal muscle mass or low lean body mass and the
occurrence of chemotherapeutic toxicity and CDLT. Patients most at risk appear
to be those with a disproportionally low skeletal muscle mass and
disproportionally high fat mass (*sarcopenic obesity*). The rationale behind
this, is that hydrophilic chemotherapeutic agents such as platinum compounds
and capecitabine, are mainly distributed within the human body in the fat-free
mass. Skeletal muscle mass is the largest component of the fat-free mass.
Patients with a disproportionally low skeletal muscle mass may actually receive
an *overdose* in chemotherapy, due to the distributional properties of the
chemotherapeutical drug.

A recent retrospective study conducted in the UMC Utrecht in patients with
locally advanced HNSCC undergoing CRT with cisplatin indeed found an
association between low skeletal muscle mass and the occurrence of chemotherapy
related toxicity. In this study, approximately 50% of patients had low skeletal
muscle mass. Patients with low skeletal muscle mass were more than three times
more likely to develop CDLT compared to patients with normal skeletal muscle
mass (44.3% vs. 13.7%). Patients with low skeletal muscle mass received a
significantly higher chemotherapy dose per kilogram estimated total lean body
mass than patients with normal skeletal muscle mass (4.6 mg/kg versus 3.8 mg/kg
estimated lean body mass). Cisplatin dose is currently calculated using a
patient*s body surface area (BSA), which does not take into account abnormal
body composition.

With this prospective study, we aim to investigate the relationship between
skeletal muscle mass and cisplatin plasma pharmacokinetics in HNSCC patients
treated with conventional primary and postoperative CRT with cisplatin. It is
designed to be a proof-of principle study of cisplatin pharmacokinetics and its
relationship with skeletal muscle mass. We hypothesize that there is a better
association between skeletal muscle mass and cisplatin pharmacokinetics than
between BSA and cisplatin pharmacokinetics. We hypothesize that currently
patients with an abnormal body composition, for instance low skeletal muscle
mass, are incorrectly dosed when dosing of cisplatin is based on BSA, because
BSA does not take into account abnormal body composition. From our research,
and from knowledge of cisplatin pharmacokinetics, we believe that a cisplatin
dosing scheme based on skeletal muscle mass may be a better alternative to the
conventional dosing method using BSA. The direct relationship between cisplatin
plasma concentration and clearance and skeletal muscle mass has however not yet
been described. This study should provide the basis needed to initiate a novel
cisplatin dosing method based on skeletal muscle mass. This may lead to a more
fitting and personalized cisplatin dosing regimen with less acute toxicity,
which may in turn have a beneficial effect on survival and quality of life of
HNSCC patients.

This study is designed as a monocenter prospective observational cohort study
in HNSCC patients receiving primary or postoperative CRT. All patients will
receive standard-of-care CRT with curative intent. There will be no
experimental treatment.

Quantitative data on skeletal muscle mass, cisplatin drug dose and cisplatin
plasma clearance will be collected, as well as quantitative and qualitative
measures concerning experienced treatment related toxicity. Skeletal muscle
mass will be measured on diagnostically performed CT imaging of the head and
neck area and of the abdominal area according to a previously published
protocol. A 24 hour urine sample will be taken for additional renal function
assessment. In patients who undergo postoperative chemoradiotherapy, one
additional CT scan of the abdomen will be performed. Four additional blood
samples will be taken for renal function assessment, biomarker assessment and a
predose pharmacokinetics sample. Three short quality of life (QoL)
questionnaires will be conducted before, during and after treatment, to assess
QoL. During cisplatin treatment, QoL and patient experienced burden will be
measured using the USD-HH, a head and neck specific measurement tool for
patient experienced burden.

In a additional study, the association between several genetic variants and
toxicity is investigated (optional pharmacogenetics study), in collaboration
with the PGx study (protocol ID PGxLungCA01; NL53736.100.15). Possible, this
will also provide more information in the future to predict which patients will
experience severe cisplatin related toxicity and which patients will not. This
is an optional side study.

Burdens: patients will receive an additional peripheral venous catheter for
taking blood samples for cisplatin pharmacokinetic measurements. Adverse events
related to the peripheral venous catheter and venous puncture, such as a
thrombophlebitis or a heamatoma, are infrequent but may occur. Five extra 5cc
blood samples will be taken from the patient from this peripheral venous
catheter. Four other blood samples will be taken for renal function assessment
and biomarker assessment. Patients will be asked to complete 3 short quality of
life questionnaires before, during and after treatment. This will take an
estimated 15 minutes per visit. Patients will be asked to once collect urine
for 24 hours at home, before start of treatment. No other risks or burdens are
associated with this study. The estimated extra risk and burden for the patient
while participating in this study is low.
Patients who are scheduled for postoperative CRT will undergo one additional CT
scan of the abdomen (to be planned at the same time as a routine CT scan of the
head and neck area, prior to radiotherapy) for measurement of skeletal muscle
mass prior to start of chemoradiotherapy. Should there be any incidental
findings, patients will be informed of this, and will be referred to the
appropriate medical specialist for further analysis or treatment.
Benefits: there are no direct benefits of this study to participants of this
study.