Understanding Molecular Mechanisms and Identifying Key Processes in Chronic Radiation Cystitis

Abstract

Chronic radiation cystitis (CRC) is a consequence of pelvic radiotherapy and affects 5-10% of patients. The pathology of CRC is without curative treatment and is characterized by incontinence, pelvic pain and hematuria, which severely degrades patients' quality of life. Current management strategies rely primarily on symptomatic measures and have certain limitations. Thanks to a better understanding of the pathophysiology of radiation cystitis, studies targeting key manifestations such as inflammation, neovascularization and cell atrophy have emerged and are promising avenues for future treatment. However, the mechanisms of CRC are still better described in animal models than in human models. Preclinical studies conducted to elucidate the pathophysiology of CRC use distinct models and are most often limited to specific processes, such as fibrosis, vascular damage and inflammation. This review presents a synthesis of experimental studies aimed at improving our understanding of the molecular mechanisms at play and identifying key processes in CRC.

Keywords: cancer; chronic radiation cystitis; fibrosis; inflammation; molecular mechanism; radiotherapy; vascular lesions.

Figure 1

Bladder dose constraints in conformal radiotherapy as a function of the percentage of whole bladder exposed. Establishing the dose constraints for the bladder for a given surface area makes it possible to assess a dose-volume effect on urinary toxicity. The tolerance dose is often expressed as follows: Vx < Y%, which means that the dose X Gy must not be delivered in more than Y% of the V volume of the organ at risk [9,10].

Figure 2

CRC symptoms are a function of the dose and the surface area of the bladder irradiated. This Figure summarizes our knowledge regarding chronic lesions of the bladder for 3DCRT and IMRT for urinary toxicity. The percentage of grade 2 or 3 lesions for a dose range from 50 to 80 Gy is indicated for 5 and 10 years after radiotherapy.

Figure 3

Decision tree for the management of chronic radiation cystitis and its treatment.

Figure 4

Relationship between the main mechanisms involved in CRC.

Figure 5

Abnormalities in urothelium regeneration and loss of impermeability.

Figure 6

Endothelial activation induces vascular permeability and tissue infiltration and stimulates a pro-thrombotic and pro-inflammatory phenotype that leads to thrombosis and leukocyte recruitment.

Figure 7

Synthesis of knowledge on the CRC and avenues for future study.

Figure 8

Hypothesis of CRC mechanisms in red. The first step is urothelium destruction mediating hyperplasia, cellular edema or atrophy. The secretion of inflammatory factors produced by urothelial injuries (TNF-α, IL1-β, IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2)) induces enrolment and stimulation of immune cells (mast cells). Mast cells secrete VEGF and tryptases, which induce vascular damage and imperfect vascular regeneration, telangiectasia, amplified vascular permeability, hematuria. This leads to the release of albumin. Albumin strengthens the secretion of pro-inflammatory factors which increase inflammation and may lead to the preservation of urothelial injuries. Mast cells, through the secretion of NGF, mediate the hyperactivation of nerve fibers. Secretion of TGF-β could mediate excessive deposition of ECM (collagen I and III, fibronectin) in the submucosa and smooth muscle. Black arrows indicate specific mechanisms of CRC, blue arrows designate shared mechanisms between CRC, interstitial and hemorrhagic cystitis; and red arrows specify hypotheses of how radiation cystitis may operate based on mechanisms of both interstitial and hemorrhagic cystitis.