Post-cancer bladder conditions - Complication of oncotherapy

Hemorrhagic cystitis is a collective name for conditions in which the bladder is inflamed, and its mucosa is bleeding. By the name “cystitis”, many experts label different conditions in which bacterial infection is not present because the phenotypes of these conditions are similar or identical. The bleeding can be microscopic (grade 1), visible (grade 2), visible with small clots (grade 3), or clots big enough to block the flow of the urine (grade 4).1 Besides the bleeding, the most common symptoms are: increased voiding frequency and urgency, nocturia, pain (especially during the voiding), and the loss of the bladder control. Infections often occur as a complication, too.

Some bacterial infections can cause hemorrhagic symptoms, but most patients respond to the antibacterial treatment; therefore, these infections rarely lead to chronic and/or recurrent HC. Certain compounds used in the industry (e.g. aniline and toluidine) can cause HC as well. The condition usually ceases to exist once the patient stops being exposed to the toxin.2 A couple of viruses may cause HC; however, the condition mostly develops either at a very young age (in which case it disappears in a couple of days), or if the patient’s immune system is severely compromised, e.g. after bone marrow or renal transplantation.3

Nevertheless, the two most common situations in which hemorrhagic cystitis emerges are associated with widely used methods of oncotherapy. It can develop after chemotherapy or radiotherapy. Thus, these conditions are often named chemotherapy cystitis and radiation cystitis, respectively. It should be pointed out that the definition of hemorrhagic cystitis is vague, and there are differences between authors and countries; several diseases are labeled as HCs regardless of their cause. Here, by this concept, the latter two, post-cancer conditions should be meant.

Certain chemotherapeutic drugs particularly frequently cause HC, especially oxazaphosphorine compounds such as cyclophosphamide and ifosfamide. These drugs are widely used in several chemotherapeutic protocols, including treating solid tumors and lymphomas.4,5

It is worth pointing out that considering the 10 most common cancers6 in the USA, cyclophosphamide and/or ifosfamide can be administered for the following conditions (frequency is in parentheses) breast cancer (1st), lung cancer (2nd), bladder cancer (6th), Non-Hodgkin’s lymphoma (7th), leukemia (10th). Regarding leukemia, there is a 30% chance for developing cystitis as a side effect.7 Moreover, these are not the only chemotherapeutic drugs that can cause HC.

The data on the incidence of HC among the patients treated with these drugs are controversial; it is said the occurrence is between 7–53%, about 0.6–15% of the patients experience severe bleeding.8 Indeed, in many cases of the cancer treatment, the toxic effect that the drug expresses in the bladder limits the dosage. The incidence of radiation cystitis is 11–20% after the radiotherapy of the pelvic area.9

In case of cyclophosphamide and ifosfamide the symptoms generally occur after the first dose is administered and last for 4–5 days.10 On the other hand, certain other compounds like busulfan may trigger chemo-cystitis years after the exposure11, and the adverse effect of a radiotherapy presenting as radiation cystitis may occur 10 or 20 years later, too.12

Current guidelines emphasize the importance of prevention. Hyperhydration, continuous bladder irrigation (saline, with or without alkalization), hyperbaric oxygen therapy, administering mesna (a sulfhydryl compound), or intravesical sodium hyaluronate (for GAG-layer replenishment) are the most commonly used methods.13,14,15,16 However, the data on their efficacy are controversial.

According to most guidelines, once the condition has been diagnosed the suggested treatment greatly depends on the severity of the state (e.g.17,18). Hemodynamic stability must be maintained in all cases, which makes blood transfusion often necessary.

In mild condition hydration, intravenous diuretics, pain medication and anticholinergic bladder medication may be sufficient. Continuous bladder irrigation is considered to be effective, too.

In more severe cases, among other methods, intravesical treatment is frequently applied. The therapy of chemo-cystitis usually lasts for some days, whereas for radiation cystitis for six months or even more.19 There are several agents known for preventing bleeding. Aminocaproic acid (which is similar to amino acid lysine) inhibits plasminogen activation, which increases blood clotting.20 Alum (aluminum ammonium sulphate or aluminum potassium sulphate) causes protein precipitation and decreases capillary permeability.21 Silver nitrate causes chemical coagulation22. Formalin, which is highly toxic, is used only if the patient has not responded to any other treatments; according to some guidelines, fulguration of the affected areas should be performed before that.

In the later years, therapists have started focusing on GAG-layer replenishments, too. Hyaluronic acid, chondroitin sulphate and pentosan polysulfate sodium have already been used in the therapy of HC.23,24,25. Prostaglandin and estrogens have been administered as well – the results are controversial, though26.27,28.

Administering GAG-layer replenishments with the UroDapter® is definitely an effective method regardless of the indication itself.