Discussion
Our patient developed grade 3 CTCAE HC, which resolved completely with supportive care. Chemotherapy-induced HC generally resolves upon withdrawal of the offending agent, along with the treatments described above. It has a favourable prognosis when compared to HC caused by pelvic radiotherapy, which can recur for many months post-treatment. Complications are rare in chemical-induced HC but can include acute kidney injury requiring dialysis, urinary tract obstruction/infection, bladder perforation and death4. Long-term effects include bladder and upper tract fibrosis as well as reduced bladder capacity. In paediatric patients, increased mortality is linked to catheterisation, need for dialysis and presence of BKV9.
Infective agents were ruled out in this case. Urine culture was negative with no evidence of pus or white cells/organisms on microscopy. The absence of pyuria has a negative predictive value of near 90%11. BKV, adenovirus and CMV have been implicated in the pathogenesis of HC12,13 and serology for all was negative.
Pelvic radiotherapy is a known cause of HC. Proton beam therapy, which is increasingly used for medulloblastoma in a paediatric population, allows for more precise treatment than traditional photon radiotherapy due to the Bragg peak phenomenon14 and therefore reduces the damage done to adjacent organs and tissues. Craniospinal irradiation is carried out to the level of L1 vertebrae and is therefore sufficiently removed from the bladder to rule out. There is no evidence in the literature that HC can be caused by distant radiotherapy.
A literature review regarding each of the medications the patient was taking (levomepromazine, omeprazole, ondansetron and paracetamol) revealed one unrelated result when searched with HC on Pubmed. Accidental administration of cyclophosphamide was excluded after thorough investigation by pharmacy and nursing staff.
It is possible that the chemotherapy agents the patient received before HC developed are culprits. Vincristine is mostly hepatically metabolised15 and is commonly used in many chemotherapeutic regimes and is therefore unlikely to be the cause. Lomustine is metabolised renally, but does not typically cause any renal issues, unless used for a prolonged period16.
Cisplatin is a platinum-based alkylating agent used for many malignancies and is well documented to cause nephrotoxicity due to accumulation in renal tubules17. The co-transporter protein OCT-2 has been identified as a key protein for the uptake of cisplatin into renal cells, and cisplatin competitively inhibits other substrates that are normally taken up via OCT-2. Inside the cell, there are a myriad of mechanisms whereby cisplatin can cause apoptosis/necrosis of the cell, including upregulation of p5318. OCT-2 receptors are also found in the urothelium19, so it follows that cisplatin could be taken up in a similar way in the bladder and cause inflammation and necrosis, leading to HC. In addition, carboplatin, a similar akylating agent, which can be substituted with cisplatin in the CCLG treatment guideline, has been mentioned in one paper as a potential cause3. Another case reports HC following combination chemotherapy with bleomycin, vinblastine, cisplatin and etoposide20.
Given the number of causes for HC, it is possible that cisplatin-induced HC has been underreported. Adenovirus is common among the general population and it is not hard to imagine a rare patient with cisplatin-induced HC being co-infected with adenovirus and the condition being falsely attributed to the known cause.