CT findings in patients with Cabazitaxel induced pelvic pain and haematuria: a case series

Background Haematuria and pelvic pain are recognized and documented adverse reactions related to Cabazitaxel use. To date there has not been any documentation of imaging findings in patients with this presentation. Cases We report a case series of five patients who experienced these symptoms while on Cabazitaxel and were all found to have very similar urothelial changes on CT. The patients were noted to have ureteric and renal pelvic dilatation along with urothelial enhancement (in those who had post contrast imaging). All of these changes were noted to be reversible in those who had follow up imaging after cessation of Cabazitaxel and initiation of a short course of steroids. Conclusion This case series helps demonstrate the pathological reversible urothelial inflammatory changes that may be occurring in patients experiencing haematuria and pelvic pain on Cabazitaxel therapy. These changes may relate to direct toxic effect of drug metabolites, a radiation recall type phenomenon or a combination of both.


Background
Cabazitaxel is an antineoplastic agent currently indicated for the treatment of adult patients with hormone refractory metastatic prostate cancer, who have previously been treated with a Docetaxel containing regime. It works primarily through disruption of the microtubular network in cells which in turn inhibits mitotic and interphase cellular functions. Once administered intravenously Cabazitaxel is primarily metabolized in the liver (>95%) by mainly CYP3A isoenzyme (up to 90%). The majority of excretion is in faeces as numerous metabolites with less than 4% of the dose excreted by the kidneys [1].
The incidence of haematuria and pelvic pain with Cabazitaxel therapy is estimated to be 16.7% and 1.9% respectively [1].
We report a series of five cases of Cabazitaxel induced pelvic pain and microscopic haematuria with characteristic pattern of urothelial inflammatory changes on CT at the time of symptoms. All patients had a history of prior pelvic radiotherapy, uncomplicated treatment with Docetaxel and exclusion of urinary tract infections at the time of presentation.

Case presentation
All patients in our series tolerated at least 5 cycles of Cabazitaxel prior to onset of symptoms, which included a varying description of pelvic pain with microscopic haematuria. Table 1 shows a clinical summary for each patient (cases [1][2][3][4][5]. Four of the patients in the series (cases 1-4) had whole pelvis radiotherapy and one patient (case 5) had radiotherapy only to the right hemi-pelvis (none had abdominal radiation). Corresponding to this, cases 1-4 (see Figs. 1 2 3 and 4) showed urothelial inflammatory changes bilaterally on CT, while case 5 (see Fig. 5) showed urothelial inflammation only on the right side.
Three out of the five patients in this group had improvement of symptoms with cessation of Cabazitaxel and initiation of a short course of steroid therapy, while the other two patients improved with Cabazitaxel cessation alone. Out of all five patients, two (one who had steroid therapy and one who did not) were able to be restarted on Cabazitaxel therapy without recurrence of significant symptoms.
Follow up imaging was conducted on two of the patients (cases 3 and 4) after resolution of pelvic pain and haematuria. These scans revealed significant improvement in the urothelial inflammatory changes supporting the reversible nature of these effects both clinically and radiologically.

Discussion
Through this case series we are providing imaging based evidence of reversible urothelial inflammatory changes occurring in patients experiencing pelvic pain and haematuria while on Cabazitaxel therapy.
While reversible side effects such as pelvic pain and haematuria have been documented related to the use of Cabazitaxel [1], to our knowledge this is the first time that such extensive reversible urothelial inflammatory changes have been noted on imaging.
We hypothesise these changes to be due to either direct toxic effect of Cabazitaxel (or its metabolites) on the urothelium or the provocation of radiation recall syndrome or a combination of both.
The reversibility of inflammatory changes following Cabazitaxel cessation is compatible with both drug toxicity and radiation recall syndrome [2]. Very limited renal excretion of Cabazitaxel/metabolites [1], attenuated recurrence of symptoms following reinitiation [2,3] and the presence of trial data showing  positive correlation between pelvic radiation and haematuria [4,5] in patients treated with Cabazitaxel, however, all favour this to be related to radiation recall. We feel that the unilateral nature of urothelial inflammatory changes in case 5 (corresponding to the side of hemi-pelvic radiation) also further supports the possibility of a radiation recall syndrome rather than drug toxicity (where one would expect inflammation to be bilateral in all cases).
Although the timing of symptom onset to beyond 5cycles of treatment and involvement of the entire urothelium rather than just the radiated pelvic regions is atypical for radiation recall syndrome, it is still possible for such a presentation to occur [2,3,6]. Certainly the extension of inflammatory change beyond the original radiation field is an accepted entity [6,7].
There is at least one case series we are aware of that has histologically shown urothelial inflammation from Cabazitaxel induced radiation recall syndrome [8]. Whilst our case series exhibits some atypical features we feel the most likely cause for these inflammatory change is a radiation recall syndrome.
It must be noted that if this is indeed a radiation recall syndrome while successful re-initiation is possible (as in our case series), there is also the possibility of severe symptom recurrence at re-initiation [6] and caution must be taken.
We hope our observations will help to improve assessment and management of patients experiencing pelvic pain and haematuria while on Cabazitaxel treatment.
Abbreviation CT: computed tomography