Oxaliplatin is a third-generation platinum derivative used commonly to treat various solid organ malignancies, including colorectal, ovarian, and pancreatic cancer.1-4 Recently, oxaliplatin-based chemotherapeutic regimens have played an important role in the treatment of advanced pancreatic cancer. The most frequent adverse effects of oxaliplatin are peripheral neuropathy characterized by acute reversible paresthesia. Although the ototoxic effects of cisplatin are well recognized, there are few reports on oxaliplatin. This paper reports the second case report of oxaliplatin-related ototoxicity in pancreatic cancer. A rare case of irreversible unilateral hearing loss occurred in a 48-year-old female after the intravenous infusion of oxaliplatin for the treatment of pancreatic cancer.

A 48-year-old woman presented with jaundice and an itching sense with a 3-week duration. Her prior medical history was unremarkable. An abdominal CT scan revealed a 2.5 cm sized mass in the pancreatic head, causing diffuse bile duct and pancreatic duct dilation. MRI confirmed a 2.5 cm sized mass in the pancreatic head with diffuse pancreatic duct dilatation. CT and MRI images showed the tumor abutting the superior mesenteric vein, suggesting a borderline resectable cancer. Endoscopic ultrasonography-guided fine-needle aspiration confirmed an adenocarcinoma. Endoscopic retrograde cholangiopancreatography was performed, and a plastic stent was placed into the bile duct for biliary decompression. With no evidence of a distant metastasis by PET, neoadjuvant chemotherapy was planned using a FOLFIRINOX regimen (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m², fluorouracil 400 mg/m² bolus infusion, followed by fluorouracil 2,400 mg/m² as a 48-hours continuous infusion), which was repeated every 14 days.

A follow-up CT scan after the 4th cycle of chemotherapy confirmed stable disease, and chemotherapy was continued. One week after the 6th cycle of chemotherapy, however, she visited the emergency room because of febrile sense, nausea, and vomiting.

Thirteen days after the 6th cycle of chemotherapy, she complained of tinnitus, dizziness, fullness, and hearing impairment of her left ear. She was referred to the otolaryngology section for an auditory evaluation. Neither the vestibular function test nor brain MRI revealed the cause of the hearing damage. Pure tone audiometry showed severe sensorineural hearing loss of the left ear (Fig. 1). With no other obvious cause of the hearing damage, oxaliplatin was suspected to be the source of the sudden hearing loss; the cumulative dose of oxaliplatin was 510 mg/m². Although high dose intravenous steroid therapy is the treatment of choice for sensorineural hearing injury, she received intratympanic steroid injection therapy due to the possibility of exacerbating the infection. The follow-up PET scan showed a decreased FDG uptake of pancreatic head cancer without evidence of distant metastasis. She underwent pylorus-preserving pancreatoduodenectomy for pancreatic cancer. A R0 resection was done for pancreatic cancer and the final TNM stage of pancreatic cancer was III (T2N2M0). Follow-up pure tone audiometry 1 month later showed no interval change. Gemcitabine-based adjuvant chemotherapy was performed for nine months. The follow-up PET scan performed after 11 months from surgery revealed FDG hot uptakes at the operation site and left supraclavicular station, indicating tumor recurrence. Fine needle aspiration of the left supraclavicular lymph node confirmed a metastasis. At this point, there was no significant clinical improvement of unilateral hearing loss.

Oxaliplatin is a new generation of platinum-containing derivatives that derives their activity by forming covalent bonds with DNA, thereby inhibiting DNA synthesis.5 Platinum-based chemotherapeutic agents, such as cisplatin, carboplatin, and oxaliplatin, are widely advocated for the treatment of a variety of malignancies, including colorectal and pancreatic cancer.1,3,4 Although oxaliplatin has extensive therapeutic potential, its use can be limited by its significant adverse effects, especially neurotoxicity.6 Oxaliplatin has often been associated with transient peripheral neuropathy and persistent neurosensory loss. Acute neurotoxicity with oxaliplatin, which frequently manifests as oral paresthesia or a tingling sensation of the extremities immediately after infusion, usually resolves spontaneously.3 On the other hand, persistent neurotoxicity can occur when platinum drugs accumulate in the dorsal root ganglia.7,8

Persistent hearing loss and tinnitus can occur in cases of platinum-based chemotherapy-induced inner ear toxicity. Platinum-based agents often damage the outer hair cells in the organ of Corti and the vascularized epithelium in the lateral wall of the cochlea and stria vascularis.9,10 The organ of Corti of the inner ear has a blood-labyrinth barrier that blocks the transport of platinum drugs to the perilymphatic space.10 A previous animal study by Hellberg et al.10 reported that the difference in the cochlear pharmacokinetics might result in substantially different ototoxic profiles. A remarkable difference in the uptake of antitumor agent into scala tympani perilymph fluid and total platinum concentration in cochlear cells have also been reported.10 The difference in cochlear kinetic and cellular uptake in the hearing end organs can explain the different ototoxicities of the platinum-derivatives.11 Therefore, the lower cochlear uptake of oxaliplatin than cisplatin may be a reasonable explanation for the lower ototoxic potential of oxaliplatin.10,11

This paper provides a summary of the five published case reports of oxaliplatin-related ototoxicity (Table 1). Malhotra et al.3 reported the first case of ototoxicity, which occurred after a single intravenous infusion of oxaliplatin for a colorectal malignancy. Of the five cases reported, hearing loss developed in four cases,1,4,3,12 and three cases, unfortunately, resulted in irreversible hearing damage, as in the present case.3,4,12 In one case of hearing loss, the patient continued chemotherapy with oxaliplatin even after developing hearing loss, and the hearing loss was irreversible.4 In the other three cases of hearing loss, chemotherapy with oxaliplatin was discontinued, and slight improvement of hearing loss was noted only in one case.1,3,12 Even after discontinuing oxaliplatin after the development of hearing loss, recovery from hearing loss was not observed in current case. A decision about whether to switch or discontinue chemotherapy after ototoxicity should be made using a multidisciplinary approach. Interestingly, four out of the five cases involved female patients, as with current case, but no plausible explanation for this gender difference has been proposed.3,4,12,13 Furthermore, these reports showed that oxaliplatin-related ototoxicity could occur at any age and any stage of treatment. Nevertheless, the rise in cumulative dose increases the risk of hearing damage. In the present case, the sensorineural hearing loss occurred after the 6th cycle of the FOLFINOX schedule.

Physicians should consider that oxaliplatin can be ototoxic, even though the risk is comparatively low. Patients treated with an oxaliplatin-based regimen should be monitored closely during treatment for the early diagnosis of potential hearing loss. Further study is warranted to elucidate the risk factors, temporal relationship, and dose-dependency for oxaliplatin-induced ototoxicity.