Anesthesia for Transurethral Resection of Bladder Tumors in Patients with Neuropathy Caused by Balloon-Occluded Arterial Infusion Treatment: A Retrospective, Observational Study

Background: A novel bladder preservation therapy has been developed for patients with muscle-invasive bladder cancer called the Osaka Medical College (OMC) regimen. This regimen comprises balloon-occluded arterial infusion (BOAI) of an anticancer agent and with or without concurrent hemodialysis. Anticancer agents, such as cisplatin, can cause neurotoxicity, leading to peripheral neuropathy. This study aimed to investigate the occurrence of neuropathy after BOAI followed by a second transurethral resection of a bladder tumor (TURBT). We also aimed to investigate the effects of general and spinal anesthesia on neuropathy. Methods: We performed a retrospective, observational study on 57 patients (49 men, 8 women, median age: 65 years) with bladder cancer who underwent a second TURBT after BOAI. TURBT was initially performed for diagnosis and then patients received the OMC regimen at 4-5 weeks after this first TURBT. Patients had general or spinal anesthesia for TURBT. For BOAI, an intra-arterial catheter with two occlusion balloons was used and inserted into the posterior trunk of the internal iliac artery. Cisplatin was infused through this catheter over 1 hour. Hemodialysis was simultaneously performed in patients (n=16) with a creatinine level >1.5mg/ dl. Radiation therapy was then performed in the pelvis. Patients underwent a second TURBT at 6 weeks. Results: Seven of 57 patients had neuropathy. Symptoms caused by BOAI in the lower extremities were pain, numbness, and tingling. Although none of the treatments for neuropathy were particularly effective, the combination of tramadol and acetaminophen reduced tingling in one patient. No patients had adverse events of grade 3 or 4. Two patients who had abnormal sensation before the second TURBT underwent general anesthesia to avoid any further deterioration. Conclusion: This study showed that neuropathy occurs after BOAI of cisplatin for bladder cancer. Although there was no deterioration in sensation of the lower extremities in patients who had a second TURBT under general or spinal anesthesia, further deterioration in sensation is possible. Therefore, spinal anesthesia should be avoided in patients who have neuropathy due to BOAI. Trial Registration: This study was registered in the Japanese Official Clinical Trial Registry (trial registration number: JMAIIA00171) and the registration date was 13 March 2014.

regimen. Cisplatin in a nonprotein-bound form exerts its antitumor activity and dissipates quickly after administration. The half-life of cisplatin is normally less than one hour, and it decreases to below the detection limit four hours after injection [1,2]. Because the molecular weight of protein-unbound cisplatin is similar to that of creatinine, HD can provide efficient removal of cisplatin. Azuma et al. reported that approximately 95% of free Pt was removed by HD via the bilateral common iliac veins during BOAI. [3]. This can provide less toxicity into systemic circulation. A common side effect of cisplatin is neurotoxicity [4,5] leading to chemotherapy inducedperipheral neuropathy. This dose-dependent toxic neuropathy is associated with distal paresthesias, affecting the hands and feet, and often starts within 1 month of initiating cisplatin treatment and continues after cessation of the chemotherapy. Accumulation of cisplatin in dorsal root ganglion neurons in the form of platinum-DNA adducts5 is thought to be one of the primary mechanisms of neurotoxicity [6]. We have found neuropathy in some patients after BOAI treatment. Although strong pain tended to disappear, tingling and numbness continued. Direct neurotoxic effects of cisplatin, small vessel injury from cisplatin, and blockage of blood flow cause neuropathy [7,8]

OMC Regimen and BOAI Therapy
Patients underwent complete TURBT in order to be diagnosed.
Patients received the OMC regimen at 4-5 weeks after the first TURBT.
All of the patients who received the OMC regimen had a neutrophil count of 1500/μl, platelet count of 100,000/μl, creatinine level of 3.0mg/dl (265.2μmol/l) an Eastern Cooperative Oncology Group performance status of 0-2, and no prior radiotherapy or systemic therapy for bladder cancer [9]. In order to perform intra-arterial infusion procedure, an intra-arterial catheter equipped with

Results
A total of 57 patients underwent a second TURBT after BOAI.  These two patients had already taken loxoprofen before the entire treatment. These two patients underwent a second TURBT under general anesthesia to avoid deterioration of sensation.  deteriorated sensation and did not find any deterioration. BOAI for bladder cancer via the internal iliac artery is widely spreading in use among hospitals worldwide as a treatment for cancer. This is because this procedure can deliver anticancer drugs with a high concentration only to the bladder. Embolization in the arteries of the lower extremities, ulcers and dermatitis, and sciatic neuralgia have been reported as adverse effects of BOAI [8,[12][13][14]. Nerve injuries caused by intra-arterial infusion of cisplatin are a direct neurotoxic effect of cisplatin and chemotherapy-induced small vessel injury, with subsequent plexus or nerve infarction [7].
Sensory nerves are usually damaged [8]. BOAI has the potential to cause nerve injury at a high rate because the remaining cisplatin spreads to distant arteries after the release of blood supply. HD can reduce the possibility of neuropathy occurring. However, our study lacks the data to conclude that HD reduced neuropathy. In addition, blockage of blood supply is the main reason for the occurrence of neuropathy [8]. Blood supply to the lower extremities was stopped for longer than 1 hour in our present study and it would have Therefore, the most appropriate anesthesia should be determined and explained to these patients.

Conclusion
This study showed that neuropathy occurred in the lower extremities after BOAI of cisplatin for bladder cancer. BOAI caused neuropathy, with symptoms of numbness, tingling and pain. Although there was no deterioration in sensation of lower extremities in patients who had a second TURBT under general or spinal anesthesia, there was a possibility of further deterioration in sensation. Spinal anesthesia should be avoided in patients who have neuropathy caused by BOAI.

Ethics Approval and Consent to Participate
The Ethics Committee of Osaka Medical College approved the study protocol (reference number: 1357), which waived the requirement for informed consent because of the retrospective design of the study.

Authors' Contributions
Junko Nakahira designed and carried out the study and drafted the manuscript. Shoko Nakano collected the data and helped to draft the manuscript. Toshiyuki Sawai participated in the design of the study and performed the statistical analysis. Yu Miyazaki and Shunsuke Fujiwara helped to draft the manuscript. Toshiaki Minami conceived the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.