Table 1.

Frequently reported cisplatin-induced adverse sequelae.

Toxicity	Acute and Chronic Complications	Frequency (%)	Pathophysiology
Nausea/Emesis	• Therapy-related anxiety • Anticipatory chemotherapy-induced nausea/vomiting • Fatigue and weakness • Weight loss, dehydration and loss of appetite • Bone fractures and tears to the throat	Acute symptoms occur in > 90% of patients when antiemetic prophylaxis is not administered (14). Delayed symptoms occur in 60–90% of patients under the same conditions (77).	Perturbs the lining of the gastrointestinal tract, which subsequently promotes Ca2+-dependent exocytic release of serotonin from enterochromaffin cells (15). Successful binding of serotonin to its receptors on the vagal afferent neurons activates the chemoreceptor trigger zone and vomiting center that promote the initiation of the emetogenic response.
Ototoxicity	• Irreversible sensorineural hearing loss • Tinnitus	Some degree of hearing loss occurs in 75–80% of patients (5, 23), while 13–18% develop severe-to-profound hearing loss (4–6). Symptoms of tinnitus occur in approximately 40% of patients (6), with 13–22% experiencing severe tinnitus (6, 8).	Increases reactive oxygen species concentrations and depletes antioxidants used for detoxification (90–92). Cisplatin also activates big conductance potassium channels in spiral ligament fibrocytes (SLFs), which adversely disrupt the electrochemical gradient within cells and trigger apoptosis (93). The cochlea retains cisplatin for months to years after treatment, with accumulation being particularly high in the stria vascularis, the SLF-containing region vital for the maintenance of endolymph ionic composition (94). Platinum-DNA adducts have been detected in the hair cells of the cochlea and the marginal cells of the stria vascularis. Since these cells do not proliferate, platination of mitochondrial DNA (mtDNA) is considered responsible for toxicity (4, 9).
Neurotoxicity (Peripheral Neuropathy)	• Persistent peripheral sensory neuropathy • Reduced physical activity and weight gain	Peripheral sensory neuropathy occurs in 36–38% of patients. (48, 49). Almost all patients who receive a cumulative dose of 500–600 mg/m2 experience nerve damage (33).	Accumulates in the dorsal root ganglia of the spinal cord and peripheral neurons via passive diffusion or metal transporters. Forms DNA adducts and inhibits DNA repair pathways that ultimately induce p53-mediated apoptosis via Bax activation (95). The affinity of cisplatin for mtDNA may help explain the clinical quandary of coasting, as the absence of the nucleotide excision repair (NER) in the mitochondria could potentiate a gradual attrition of mitochondria, subsequently reducing ATP levels that neurons require to maintain their functional activity (96).
Myelosuppression	• Cytopenias • Residual bone marrow injury and reduction in hematopoietic stem cell reserves • Potential susceptibility to secondary leukemia	Between 25–30% of patients develop symptoms of myelosuppression, while 5–6% (66) are diagnosed with severe myelosuppression.	Elicits both genotoxic effects and oxidative stress to deplete blood counts(68). Patients may also develop residual bone marrow injury in which there is a sustained reduction in hematopoietic stem cell reserves due to self-renewal impairment (69, 70).
Nephrotoxicity	• Acute kidney injury • Hypomagnesemia • Permanent kidney damage	Acute kidney injury occurs in 20–30% of patients (12). Hypomagnesemia manifests in 40–100% of patients.	Active transport through Oct2 and Ctr1 (97, 98) induces toxicity primarily in the renal proximal tubules (11). Mechanisms of damage include endoplasmic reticulum stress and mitochondrial dysfunction leading to oxidative stress, as well as inflammation mediated by tumor necrosis factor and other chemokines (11, 12).