Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02425397 |
| Other study ID # |
2010-A00405-34 |
| Secondary ID |
2010-A00405-34 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 27, 2011 |
| Est. completion date |
January 5, 2016 |
Study information
| Verified date |
April 2021 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
A limited number of relatively contradictory studies have suggested that the development of
serious ototoxicity in children treated with cisplatin or, more rarely, carboplatin could be
partly related to genetic risk factors affecting detoxification enzymes and membrane
transporters of platinum derivatives. The objective of this study is therefore to identify
genetic variants associated with the development of platinum ototoxicity in patients treated
with cisplatin or carboplatin (minimum follow-up of 3 years) for one of the following
diseases: neuroblastoma, hepatoblastoma, retinoblastoma, malignant germ cell tumour,
osteosarcoma, high-risk or recurrent Wilms' tumour, non-parameningealrhabdomyosarcoma. A
total of 180 patients, corresponding to 60 cases with grade 3 or 4 ototoxicity and 120
controls with no signs of ototoxicity (separate complete audiograms for each ear) will be
included. A saliva sample will be used to obtain DNA for pharmacogenetic studies. The value
of this study will be to define a population at high risk of developing ototoxicity in order
to adapt treatment, or even develop preventive treatment of ototoxicity based on antioxidant
medications
Description:
- Platinum derivatives and their toxicity Cisplatin, carboplatin, and oxaliplatin are
major cytotoxic agents used in the treatment of many types of cancer. They exert their
cytotoxic action by forming DNA adducts. However, their structural differences confer
different pharmacokinetic and pharmacodynamic properties, and especially different
toxicity profiles. Cisplatin induces a risk of nephrotoxicity at all ages, peripheral
neuropathy of the extremities in young adults and a risk of ototoxicity in children.
Carboplatin is essentially haematotoxic and sometimes ototoxic (especially at high
doses), while oxaliplatin is essentially neurotoxic. Ototoxicity is measured by
pure-tone audiometry and is scored from grade 0 to grade 4, where grades 3 and 4
correspond to severe ototoxicity, according to the Brock grading system, the reference
system for measuring ototoxicity at the time of treatment of these children and up until
the present time (Brock et al., 1991) (Peters et al., 2000). Ototoxicity limits the
cumulative dose of platinum derivatives in children. Cisplatin remains a major drug in
paediatric oncology (osteosarcoma, high-risk neuroblastoma, malignant germ cell tumours,
hepatoblastoma, medulloblastoma, other brain tumours). Cisplatin ototoxicity is fairly
frequent and can be very severe (more than 50% of grade 1 or higher ototoxicity; 15% of
grade 3 or 4 ototoxicity) (Bertolini et al., 2004). Carboplatin, an important component
of the treatment of many embryonal tumours (neuroblastoma, medulloblastoma,
retinoblastoma) is less frequently responsible for ototoxicity (between 1 and 5% of
grade 1 or higher ototoxicity), but can nevertheless occasionally cause serious
ototoxicity (1% of grade 4) (Jehanne et al., 2009). Ototoxicity can also appear and
deteriorate for several years after treatment (median time to discovery of carboplatin
ototoxicity: 3.7 years), while no cases of recovery of high-grade hearing loss have been
reported (Bertolini et al., 2004; Jehanne et al., 2009). These ototoxicity phenomena can
have very harmful consequences for the child's social development and schooling.
Oxaliplatin will be excluded from this study, as few children are currently treated with
this molecule, which is generally not ototoxic.
- Detoxification of platinum derivatives The glutathione (GSH) conjugation pathway is
involved in detoxification of platinum derivatives and decreases their cytotoxicity by
inhibiting the formation of DNA adducts. Conjugation to GSH is ensured by
glutathione-S-transferases (GSTs), which constitute a multigenic family of enzymes
involved in phase II metabolism that inactivate electrophilic molecules by conjugating
them to glutathione, thereby promoting their elimination. GSTP1 is particularly involved
in the conjugation of platinum derivatives. Elimination of glutathione conjugates then
involves membrane transporters. These conjugates can be expelled from target tumour
cells and then eliminated, essentially in the urine, by efflux membrane transporters,
particularly MRP2 (Sun et al., 2009). Two other enzymes, thiopurine S-methyltransferase
(TPMT) and catechol O-methyltransferase, have been reported to be associated with
increased toxicity of cisplatin when their activity is decreased (Ross et al., 2009).
- Genetic factors predisposing to or protecting against the toxicity of platinum
derivatives Several GST isoenzymes present polymorphisms modifying their activity. This
is the case for the GSTM1 and GSTT1 isoenzymes, which can undergo deletions responsible
for loss of activity of the enzyme, and GSTM3, for which the GSTM3*B allele has been
associated with induction of enzyme activity by cisplatin (Peters et al., 2000). An A/G
polymorphism situated in the substrate binding domain of the GSTP1 isoenzyme in position
+313 of exon 5 (A313G) induces substitution of a isoleucine by a valine (Ile105Val).
This polymorphism is relatively frequent (about 10% of homozygous mutants in Caucasian
populations). It influences the activity of the enzyme and has been associated with
better survival of patients receiving platinum-based chemotherapy (Goekkurt et al.,
2006; Stoehlmacher et al., 2002; Sun et al., 2009). This polymorphism has also been
shown to influence the toxicity of platinum-based treatments. For example, one study
showed that the neurotoxicity of oxaliplatin was more frequent in subjects homozygous
for GSTP1 105Ile allele than in heterozygous subjects or subjects homozygous for the
GSTP1 105Val allele (odds ratio = 5.75). (Lecomte et al., 2006). This protective effect
of the mutant allele has also been demonstrated for docetaxel peripheral neuropathies
(odds ratio = 6.11) and cisplatin ototoxicity in testicular cancers in young men (Mir et
al., 2009; Oldenburg et al., 2007).
A study conducted in children demonstrated an association between GSTM1 and GSTT1
polymorphisms (presence of at least one null genotype) and the development of grade 3 or
higher toxicity related to treatment of medulloblastoma. However, this study, based on a
small sample of children (42 children, 19 of whom experienced severe ototoxicity) and
comprising patients receiving very different treatments, was unable to determine the
proportion of toxicity specifically related to platinum derivatives, as some patients also
received brain irradiation. Furthermore, this association between GST polymorphisms and
toxicity was not observed when the analysis was specifically confined to grade 3 or higher
ototoxicity. Finally, the role of GSTP1 Ile105Val polymorphism has not been evaluated in
children (Barahmani et al., 2009). To our knowledge, only one study has specifically
evaluated the potential impact of GST polymorphism on cisplatin ototoxicity in children. This
study showed a protective effect of the GSTM3*B variant, but did not observe a protective
effect of the GSTP1 105Val allele with respect to ototoxicity, as demonstrated in adults for
neurotoxicity. However, these findings were based on small sample sizes (20 patients with
ototoxicity versus 19 patients without ototoxicity) and the ototoxicity experienced by these
patients was grade 2 (8 patients) or 3 (12 patients) with no cases of grade 4 ototoxicity
(Peters et al., 2000). The results of this study therefore need to be confirmed by a study
comprising a greater number of patients, cases and controls, including patients with more
severe ototoxicity. Ross et al., studying drug metabolism enzymes, demonstrated a highly
significant association between cisplatin ototoxicity in children and genetic variants of
TPMT (rs12201199, p = 0.00022, OR = 17.0) and COMT (rs9332377, p = 0.00018, OR = 5.5).
However, as the role of these enzymes in detoxification of platinum derivatives has not been
previously reported, these results need to be confirmed by other studies with, in particular,
matching for age, exclusion of cases of grade 2 ototoxicity from the group of severe
ototoxicity, and a greater number of control patients (Ross et al., 2009). Finally, no study
has investigated the genetic factors involved in carboplatin ototoxicity in children. One
study concerning membrane transporters showed that a common polymorphism situated in the
promoter region of the MRP2 (-24C>T) transporter gene was associated with a better response
to platinum-based chemotherapy (allelic frequency: 18% of Caucasian) (Cascorbi, 2006; Sun et
al., 2009). It would be interesting to determine whether polymorphisms affecting this gene
can also modulate the toxicity of these treatments. A polymorphism of the gene coding for the
influx transporter OCT2 (c.808G>T; p.270Ala>Ser) has also been shown to be associated in vivo
and in vitro in mice with a protective effect in relation to cisplatin nephrotoxicity and
ototoxicity (Ciarimboli et al.; Filipski et al., 2009), but the potential influence of this
polymorphism on platinum ototoxicity has never been demonstrated in man. It therefore appears
very interesting to study the potential impact of this polymorphism in the context of our
study.
In summary, all of these studies clearly confirm the hypothesis that genetic factors are
involved in the predisposition of some children to experience harmful ototoxic effects of
platinum derivatives, particularly cisplatin and carboplatin. These studies also suggest the
existence of good candidate gene variants likely to be associated with the development of
this ototoxicity. However, the results of most these studies have either not been reproduced
or remain controversial, indicating the need for confirmation studies based on larger sample
sizes and more homogeneous patient groups in terms of treatment, as in the Otoplat study.
