Introduction

Pseudomyxoma peritonei is a neoplastic phenomenon with an estimated incidence of 1-3 in 1,000,000 per year [1]. It is characterized by excessive mucinous ascites that, if left untreated, result in mass compression, organ dysfunction, and malnutrition. Appendiceal cancer is the most common culprit, although this clinical syndrome may also be elicited by ovarian, pancreatic, or colorectal tumors [2].

As it stands, cytoreductive surgery and HIPEC offer the most favorable survival outcomes, although this is only appreciable in select populations due to high postoperative morbidity. Operative suitability is determined by a combination of patient and tumor factors such as baseline function, comorbidities, the extent of metastasis, and disease resectability [3]. There is therefore an impetus to investigate other avenues for management.

Unfortunately, PMP exhibits a poor response to systemic chemotherapy. This is likely attributable to the carcinogenic and chemoresistant properties of the mucinous barrier lining neoplastic cells [4].  This has prompted researchers to explore the role of mucolytic therapies in optimizing chemosensitivity, as well as disintegrating high-volume mucinous disease in non-operative candidates [5].

Mucin 2 (MUC2) is a significant constituent of PMP mucin (amongst MUC1 and MUC5AC) which has become an appealing target for mucolytic therapy. It is a glycoprotein composed of peptide, disulfide, and glycosidic bonds. Bromac, a combination of bromelain and N-acetylcysteine, has shown promise in the treatment of PMP. Bromelain is a cocktail of proteolytic and non-proteolytic enzymes extracted from the stems of pineapple plants, that hydrolyses glycosidic bonds, amides, and esters. N-acetylcysteine is an amino acid naturally found in Allium plant species which reduces disulfide bonds between MUC2 bonds. Together, they compromise the structural integrity of mucin [4,6,7]. The mucolytic effects of bromac have been demonstrated in both ex-vivo and in-vivo studies [8]. The safety of Bromac has also been demonstrated in Phase 1 trials, with the most common adverse effects including a rise inflammatory markers, febrile reaction, and pain. Serious adverse effects occurred in 12.5% of patients. These included but were not limited to, hypoalbuminemia (requiring albumin infusions), sepsis, and gastrointestinal fistulas. No treatment-related deaths were reported. [9].

Bromac has seen use in rare cases of intrathoracic PMP [10], but has never before been used in bladder involvement. This case series discusses the novel use of intravesical Bromac for the management of urinary symptoms in patients with PMP bladder invasion.

Case 1

A 41-year-old male with a background of recurrent appendiceal cancer and PMP presented to the emergency department with two weeks of increasing urinary frequency, difficulty voiding, and mucinous discharge from his urethra and rectal stump. He also reported intermittent symptoms of bowel obstruction including reduced stoma output, abdominal pain, and nausea. On examination, he was noted to have a large abdominal wall mass measuring approximately 10cm in diameter in the left mid-abdomen. A computer tomography (CT) of his abdomen and pelvis revealed lobulated lesions at the rectovesical pouch, and larger lobulated masses posterior to the rectus abdomini muscles measuring 56x118mm indicative of progressive mucinous disease (Figure 1).

 

Figure 1: Delayed portal venous CT view showing A) invasion of PMP into rectus abdominal muscles (axial view), B) Bladder and rectal stump involvement of PMP (axial view), C) PMP involvement of anterior abdominal wall (sagittal view)

This patient had a history of two previous peritonectomies in 2013 and 2015. He was planned for a re-do peritonectomy in 2021, however when informed he may have required a urostomy due to invasion of his bladder dome, he declined operative management and discharged against medical advice.

Given this patient’s aversion to receiving a urostomy, he consented to treatment with intravesical Bromac. Prior to this, a retrograde cystogram was performed, which excluded a rectovesical fistula (Figure 2).

 

Figure 2: Four axial slices of post-contrast CT cystogram demonstrating filling defect in posterior aspect of the bladder due to mucinous disease. No contrast extravasation to rectal stump noted.

The Bromac solution was prepared by mixing 100mg of bromelain with 10 ml of sodium chloride 0.9%. This was injected in 500ml of glucose 5% using a minisart syringe filter. 10ml of N-acetyl cystine was then mixed with the glucose/bromelain preparation. This was administered via a three-way catheter, which was then spigotted.

Due to symptoms of bladder fullness and urinary urgency, the patient was unable to tolerate large boluses of the Bromac solution. As such, a decision was made to administer small volumes of Bromac twice daily over three days. Given the novel use of Bromac, there were no protocolized guidelines regarding volume and length of treatment. In this case, the volume administered and duration of therapy (i.e. how long the catheter remained spigotted) were determined by patient symptoms (Table 1). Following administration of Bromac, the patient reported referred discomfort and fullness at the site of his mucinous abdominal wall invasion. He also reported dizziness and a generalized feeling of warmth – both of which were transient and self-limiting.

Table 1: Case 1 - Volume and duration of Bromac administration.

Following the three days of intra-vesical Bromac therapy, a repeat cystogram was performed (Figure 3) which showed a small decrease in mucin and no evidence of bladder wall dissolution. 7 days following his last dose of bromac, the patient reported a subjective improvement in his urinary symptoms.