Discussion:
There is only limited literature for chemotherapy toxicity in XP
patients, owing to its rarity. Sumiyoshi et al(9) reported 2 elderly
patients with XP variant with mutations in POLH gene encoding DNA
polymerase η that is involved in the trans-lesion DNA synthesis (TLS).
Both developed severe toxicity with cisplatin involving liver, kidney,
cochlea, gastrointestinal tract and bone marrow ultimately resulting in
death. Carneiro et al(10) reported another lethal nephrotoxicity
following cisplatin in a young oral squamous cell carcinoma patient with
XP. Gilbar et al(11) reported a similar toxicity with cisplatin in a
patient who seems to be the only patient that survived the fatal
toxicity. Both the later authors postulated the defective XPC gene to be
the underlying genetic defects in these 2 patients. Our index case is
the first such toxicity reported after carboplatin as per the current
literature (Table-1).
XP is characterized by defective nucleotide excision repair (NER)
pathway, that leads to excessive DNA damage by UV radiation. Booton
etal(12) found that polymorphism in XPD gene is associated with platinum
toxicity in lung cancer patients. Though in their cohort none had XP,
this observation highlights the pharmacogenomic interaction involving
the XP gene expression and platinum chemotherapy.
Platinum-DNA adduct formation is an important mechanism of its
antineoplastic activity(13). Repair of these adducts occurs by NER,
involving genes like XPA, XPB, and ERCC1-XPF(14). Recent in-vitro models
suggest that XPC gene expression increases susceptibility of colorectal
cancer cell lines to chemotherapy(15) and XPC mutations in fibroblasts
increases oxidative DNA damage(16). In most of the XP subtypes one of
the above loci are constitutionally defective and non-neoplastic cells
are also at risk of exaggerated DNA damage by Platinum compounds,
leading to toxicity.
Although the genetic subtype of the index case is not known, due to
complete absence of neurological symptoms she was clinically labelled as
XPC. Current evidence is insufficient to conclude if one or the other XP
subtype is associated with more severe toxicity to chemotherapy. Also,
it is not known whether similar toxicity is observed with anticancer
drugs other than platinum compounds. In vitro studies of cells of
various subtypes of XP can shed more light into their relative
susceptibility to anticancer agents. In conclusion, we would recommend
to withheld platinum compounds in XP patients and to closely monitor for
toxicity of other anticancer drugs if at all used.
Conflict of Interest statement: The authors declare no conflict
of interest.
Acknowledgement: We sincerely acknowledge the family of the
patient for giving us the consent to publish the case
Funding: None