Application of cryoablation in animal models of bladder and muscle-invasive bladder cancer: a narrative review of current status and future perspectives

Introduction

Bladder cancer (BC) is a complex disease with high morbidity and mortality. In patients diagnosed with BC, muscle-invasive bladder cancer (MIBC) accounts for 25%, including tumors invading the intrinsic muscle layer (T2), invading surrounding tissues of the bladder (T3), or invading adjacent pelvic organs/structures (T4) (1). High-risk non-muscle-invasive bladder cancer (NMIBC) has a probability of progressing to MIBC ranging from 25% to 50%, with risks of tumor metastasis and mortality (2).

Multiparametric magnetic resonance imaging (mpMRI), including diffusion-weighted imaging (DWI), T2-weighted imaging (T2WI), and dynamic contrast enhanced-T1 weighted imaging (DCE-T1WI), plays an important role in the diagnosis of BC (3). The proposed Vesical Imaging-Reporting and Data System (VI-RADS) is based on scores of multiple magnetic resonance imaging (MRI) sequences (4). The diagnosis of BC is then made intuitively based on the total VI-RADS scores, which is useful to determine the muscle invasion (MI) status preoperatively (5). When the tumors are located at the bladder neck/trigone/dome/posterior and anterior wall, VI-RADS has superior diagnostic performance for detecting MI. Nevertheless, in some circumstances, VI-RADS has been shown to be inferior to cystoscopy for tumors located on the lateral wall or ureteral orifice. Therefore, a combination is recommended for accurate staging (6).

Radical cystectomy (RC) is the curative treatment for patients with MIBC. Systemic chemotherapy is often required to improve outcomes before or after RC (7). However, elderly patients often present with comorbidities, rendering them unable to tolerate such extensive surgery. Urethral reconstruction diminishes the quality of life. An increasing number of patients prefer trimodal therapy (TMT), consisting of transurethral resection of bladder tumor (TURBT) followed by adjuvant radio-chemotherapy, with RC reserved as salvage therapy (8). However, TMT requires high treatment compliance from patients and necessitates close collaboration and referral within the MDT team. Moreover, the general anesthesia required for the operation of TURBT, the side effects of radio-chemotherapy, and the high cost of treatment limit the clinical acceptance rate of TMT.

TURBT combined with transiliac/bladder artery infusion chemotherapy/embolization is also an optional treatment with excellent hemostatic effect. The protocol improves objective response rates and reduces tumor volume. Compared to systemic chemotherapy, it reduces side effects and enhances the possibility of bladder preservation. However, it is a palliative treatment, and its long-term efficacy relative to that of the TMT regimen remains to be explored (9-11). Radioactive ¹²⁵I seeds emit a low dose of gamma rays, which provide continuous irradiation to the tumor tissue and are capable of killing tumor cells. In a murine bladder tumor model (12), the implantation of radioactive ¹²⁵I seeds into tumor tissues showed inhibitory effects on tumor volume and weight. However, radioactive seed implantation is also regarded as a palliative treatment after disease recurrence or metastasis, and its long-term efficacy is still poor (13,14).

Ablation has developed rapidly and has been widely applied to solid tumors of various systems. Even some of the new technologies have replaced traditional surgical protocols, diversifying the treatment of solid tumors. Its advantages include operation under local anesthesia, minimal trauma, short operation time, repeatable treatment, and short recovery time. Under the guidance of imaging devices, cryoablation effectively ablates tumor tissue, destroying target lesions while minimizing damage to surrounding organs. This technique has been widely used among solid tumors, including liver, lung, and breast cancers (15-17). Additionally, for desmoid-type fibromatosis, imaging-guided thermal ablative therapies contribute to symptom relief and have a low major complication rate (18). Nevertheless, few reported studies have investigated the use of cryoablation in BC treatment. This review discusses the mechanisms, effectiveness, and safety of cryoablation, highlighting relevant animal studies and clinical applications. It also addresses the technical aspects, challenges, and potential future directions of cryoablation in BC treatment (Figure 1). We present this article in accordance with the Narrative Review reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1174/rc).

Figure 1 Flow chart of the study. From the aspects of animal models and clinical applications, this review discusses the pathologic changes, guidance devices, organs protection techniques, and novel cryoablation devices. It also addresses the potential future directions of cryoablation in bladder cancer treatment. MIBC needs integrated comprehensive protocols. We propose a therapeutic vision for MIBC from an interventional oncology perspective. MIBC, muscle-invasive bladder cancer.

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Institutional Ethics Board of Beijing Hospital (No. 2024BJYYEC-KY028-01) and all patients provided informed consent.

We used the PubMed database to search for articles using “muscle-invasive bladder cancer”, “bladder cancer”, “cryoablation”, “cryosurgery” (Table 1). We reviewed the abstracts and content of the articles relevant to this study, which covered animal models and clinical applications in MIBC (Table 2, Figure 2). The research findings were then analyzed, compiled, and discussed in the article. We also gathered imaging data from the Minimally Invasive Tumor Therapies Center of Beijing Hospital.

Figure 2 Flow chart of the inclusion and exclusion criteria.

Animal models

Pathologic changes

Researchers have explored bladder cryoablation parameters and safety in animal models such as New Zealand rabbits, beagles, and swine. Yang et al. (19) constructed a VX2 tumor model in the bladder apex of 20 New Zealand rabbits. After successful modeling, 10 subjects were treated with cryoablation using liquid nitrogen, with the other 10 regarded as the control group. Euthanasia was performed 6-, 24-, and 48-hour, and 1-, 2-, 3-, and 4-week after cryoablation. Pathological changes, tumor infiltration depth, and metastasis were assessed in the acute, subacute, and chronic phases. At week 4, bladder stones replaced necrotic tissue at the ablation site in six rabbits in the experimental group. The ablation lesions of the remaining four rabbits were completely necrotic and liquefied. Intrapulmonary metastases were also significantly less than those in the control group. Permpongkosol et al. (20) performed cryoablation on porcine bladders using an argon-helium knife (−140 ℃) to ablate the outer plasma membrane layer and the inner mucosal layer of the bladder, respectively. They also evaluated pathological changes in the acute, subacute, and chronic phases. The results confirmed that whole-layer coagulative necrosis could be achieved either through the intravesical or extravesical route, and no bladder rupture or perforation was observed in any of the animals. The pathological changes that occur in the bladder after cryoablation mainly consist of three distinct phases. The acute phase is characterized by mucosal necrosis, full-thickness edema, vascular congestion, and capillary dilation accompanied by microthrombi. The subacute phase involves muscle necrosis, granulation tissue formation, and early scar formation. Pathologic changes in the chronic phase include thickening of the bladder wall, scar formation, muscle destruction, submucosal edema, and macrophage infiltration (19).

Guidance devices

Cryoablation of the bladder is usually performed with guidance devices. Sutherland et al. (21) evaluated the safety of cryoablation by three routes: transperitoneal, transcystoscopic, and percutaneous in porcine bladders. Of the three animals in the transcystoscopic group, two had intraoperative bladder perforation. Necropsy revealed enterocystic fistula in the third animal. The final pathologic examination confirmed whole necrosis of the bladder wall in all groups. However, percutaneous and transperitoneal routes seem to be safer and more repeatable. The presence of bladder perforation may have been due to mechanical injury caused by a rigid cystoscope or a sharp cryoprobe.

Protective medium

During cryoablation, the bladder needs to be filled with a protective medium to ensure subsequent manipulation. Natalin et al. (22) evaluated the safety of saline, CO₂, and helium as filling media during cryoablation of porcine bladders. During the two thawing cycles, bladder pressure increased significantly in all animals of the CO₂ group, with pressures ranging from 13.6 to 122.8 mmHg. In contrast, the bladder pressures in the saline and helium groups ranged from 2.1 to 17.3 mmHg and 20.1 to 27.6 mmHg, respectively. Moreover, the pressure changes in the saline, CO₂, and helium groups were 0.16, 6.96, and 0.42 mmHg/s, respectively. The bladder of 1 swine in the CO₂ ruptured during thawing, and the rupture site was a non-cryoablation site. Pathologic analysis revealed significant intramural capillary hemorrhage in the CO₂ group, compared to little histologic change in the helium and saline groups. During the thawing process, the sublimation of CO₂ may increase bladder pressure. Therefore, saline and helium are safer and more reliable protective media during bladder cryoablation. In fact, saline is preferred by clinicians because it is cheap and easily available.

Novel devices

To prevent mechanical injury to the bladder, a novel cryoballoon filled with liquid nitrogen was used to ablate the Beagle bladder and evaluate its parameters (23). Temperatures at multiple sites were measured using thermocouples. The temperature at the center of the mucosal side was −137.4 ℃, which was almost the same as the temperature at the center of the plasma side. The temperature at a distance of 1 cm from the center was −42.4 ℃ and that at the edge of the area was only slightly below the normal body temperature. The study confirmed that the device can achieve complete necrosis of the bladder layer while ensuring a safe distance of 1 cm, with minimal impact on surrounding tissues and organs. Baust et al. (24) used saline to fill the porcine bladder under the guidance of a flexible cystoscope. A cryoablation catheter was then introduced to ablate various sites within the bladder including the bladder wall, bladder triangle, ureteral orifice, and distal ureter. Bladder perforation (8.4%) occurred when the temperature of the outer bladder layer was less than −60 ℃/5 minutes (inner bladder wall lees than −100 ℃). The temperature gradient between the inner and outer layers of the bladder was 25–40 ℃. If the temperature of the inner bladder wall was less than −50 ℃, then <25 ℃ was transferred to the outer layer. Regardless of thickness (2–12 mm), a session of 1.5 minutes/−50 ℃ was able to achieve an area of approximately 1 cm in diameter and 1.2 cm in depth without the appearance of fistula/perforation. Pathologic examinations revealed that approximately 80% of the tissue within the cryoablation lesion was destroyed.

Clinical applications

Incomplete TURBT has a direct impact on the prognosis of patients with MIBC. After initial TURBT, around 70% of patients experience incomplete resection, and approximately 30% develop residual tumors at the site of resection (30). Guidelines recommend a second TURBT 4–6 weeks after the initial TURBT. Repeat TURBT can detect residual tumors in 26–83% of cases (31). Furthermore, thermal damage caused by TURBT may result in bladder tissue loss, thereby increasing the risk of perforation. Resection of the lateral wall may induce the obturator nerve reflex and result in perforation. These factors affect the optimal use of TURBT for deeply invasive lesions. In contrast, cryoablation of the bladder is relatively safe and maintains the integrity of the bladder without perforation (25). Liu et al. (25) evaluated cryoablation as an adjunctive therapy to reduce recurrence. A total of 10 high-risk NMIBC as well as MIBC (Ta–T2a) were enrolled. Among these patients, 2 had T2a stage tumors, 3 had T1 stage tumors, and 5 had Ta stage tumors. Transurethral cryoablation was performed immediately after TURBT. A cryoballoon filled with liquid nitrogen was placed through the cystoscope and expanded tightly against the tumor base. Then, 2–3 cycles of 3 min-freezing were performed. The operations were completed without complications, including bladder perforation or bladder fistula. No adverse events of grade II–IV were reported. During the 9 months of follow-up, tumor recurrence was observed in 3 patients. Only 1 patient experienced in situ recurrence. Liu et al. (26) applied Raman spectroscopy and cryoablation as adjunctive therapies to TURBT, aiming to improve treatment efficacy and reduce local recurrence. Since the phenylalanine peak and tryptophan peak are different between BC and normal bladder tissue, malignancy can be distinguished and staged. The researchers collected Raman signals from 74 BC patients and established Raman spectra, which contain normal bladder tissue and different pathological types of BC. They included 2 groups of patients in the study: 1 group accepted cryoablation after undergoing Raman scanning following conventional TURBT (TURBT-Raman-Cryo group) and the other group was treated with conventional TURBT (TURBT group). The recurrence was lower in the TURBT-Raman-Cryo group than in the TURBT group (1/27 vs. 8/26, P=0.0394).

Zhang et al. (27) reported 7 male pT4b MIBC patients with transperineal cryoablation. They performed 2 cycles of freeze-thaw cycling using an argon-filled 1.47 mm 17G cryoprobe. After maintaining −40 ℃ or a minimum temperature below −25 ℃ for 10 minutes, passive thawing was initiated until the plateau period, followed by active thawing with helium. The patients showed satisfactory tolerance with a mean blood loss of 19.29±15.92 mL (5–50 mL). Progression-free survival (PFS) was 22.00±14.61 months (3–40 months); overall survival (OS) was 85.7%, 57.1%, and 42.9% at 1, 2, and 3 years, respectively. No serious adverse events occurred. Liang et al. (28) used a 1.7-mm argon-filled cryoprobe to perform cryoablation in 23 patients with stage IV BC. Up to 4 cryoprobes were applied depending on the lesion size, with the probe tip temperature reaching −120 ℃. A maximum of 15 minutes of freezing was performed within a freeze-thaw cycle. Through 2 freeze-thaw cycles, it was observed that lesions both inside and outside the bladder cavity were completely ablated. The PFS of these patients was 14±8 months. According to Sun et al., a 1.47-mm cryoprobe was employed to perform a double freeze–thaw cycle (freezing for 10 mins, thawing for 5 min) on 32 cases of T2-T4aN0M0 bladder tumors (29). Argon/helium gas was used as a refrigerant to achieve a treatment temperature of −140 ℃. A single cryoprobe formed an ice ball 3 cm in diameter and 5 cm along the axis of the probe. Follow-up images with computed tomography (CT) were obtained at 3, 6, 12, 18, 24, 36 and 48 months after cryoablation. A total of 29 of 32 patients had 33-month follow-up (range, 6–48 months) data. Only 2 of the 32 patients were re-treated due to the detection of residual lesions, but no enhancement was observed during follow-up imaging.

Techniques for protecting organs during cryoablation

Unlike other parenchymal organs, the bladder is a cystic, hollow organ. It is more susceptible to rupture and perforation due to mechanical irritation from cystoscopy and ablation equipment, as well as edema and muscle necrosis after bladder cryoablation (24). Bladder-intestinal fistulas may form in response to extreme cold stimulation in the vicinity of the bladder. Aiming to avoid serious adverse events, researchers have attempted animal experiments and clinical applications, with the following additional goals: To improve the ablation devices preoperatively (24,26); to determine appropriate and safe ablation parameters intraoperatively and to monitor peripheral organ temperature and ice-ball growth in real time (21,27); and to suture the bladder puncture site with an isolation wrap postoperatively and the ablation target area (19,20).

Techniques for protecting organs in animal models

Yang et al. (19) used a cryoprobe via the extravesical route in the cryoablation of VX2 rabbits. At the end of the ablation, they directed the ablated area into the bladder cavity, performed a purse-string suture encasement, and then reconstructed the bladder with sutures. At the end of the experiment, the reconstructed bladder was completely healed and there was no bladder rupture perforation. Permpongkosol et al. (20) similarly performed a protective purse-string suture encasement of the puncture point after bladder cryoablation. Sutherland et al. (21) stated that cystoscopy alone without laparoscopic assistance is unsafe. The combination of cystoscopy and laparoscopy enables real time monitoring of ice ball growth inside and outside the bladder. Baust et al. (24) found that due to the specific growth properties, the ice ball did not consistently increase in size. Bladder perforation occurred when the temperature of the outer bladder wall was less than −60 ℃ (inner bladder wall <−100 ℃) and freezing time lasted 5 minutes. Therefore, it is necessary to set a temperature limitation for cryoablation to avoid bladder perforation.

Techniques for protecting organs in clinical applications

In clinical applications, Zhang et al. (27) performed cryoablation on the bladder via a perineal approach, using Doppler ultrasound to monitor the growth of the ice ball. They placed two temperature electrocouples around the lesion and rectum, respectively, to monitor intraoperative temperature. The temperature of the rectum was kept above 0 ℃ during cryoablation, and freezing was stopped when the temperature of the anterior rectal wall reached 20 ℃. Cryoballoons with soft cystoscopes seem to be favored by clinicians over cryoprobes with hard, sharp tips (24). Liu et al. (26) developed a cryoballoon in which a balloon was attached to the tip of a cryoprobe and filled after placement in the bladder. The balloon was curved to fit perfectly with the base of the tumor, resulting in a larger contact area and higher ablation efficiency. Compared to the cryoprobe, mechanical damage to the bladder wall was greatly reduced.

Others

Other bladder protection strategies could also be employed: insert a catheter to empty the bladder of urine before cryoablation; intraoperatively, inject a contrast agent into the bladder and perfuse the bladder with warm saline (Figure 3); or keep a urinary catheter for 2–4 weeks and administer prophylactic antibiotics postoperatively (29).

Figure 3 A patient with MIBC was admitted to our treatment center for palliative therapy. A urinary catheter was placed prior to cryoablation (A). The bladder was irrigated with saline. Contrast-enhanced CT showed the bladder mass, with the range of 62.17 mm × 55.63 mm. Contrast agent was injected into the bladder to improve visualization contrast (B). A 17G cryoprobe using liquid nitrogen was punctured into the mass under CT guidance. Four freeze-thaw cycles of ablation were performed on both sites (C-E). Repeat CT at the end of cryoablation showed no bladder perforation as well as bladder-intestinal fistula. A urinary catheter was kept in the bladder postoperatively and prophylactic oral antibiotics were administered (F). MIBC, muscle-invasive bladder cancer; CT, computed tomography.

Guiding and monitoring devices during bladder cryoablation

Cystoscopy, laparoscopy, and imaging devices such as ultrasound, computed tomography (CT), and MRI can be used as guided monitoring devices during cryoablation.

After TURBT, cystoscopy is usually applied through the urethral access to introduce a cryoablation device. The soft cystoscope with a cryoablation balloon allows safe ablation of lesions anywhere in the bladder, minimizing mechanical irritation to the urethra and bladder (24,32).

A laparoscope is another commonly used device, which can be used in conjunction with a cystoscope to simultaneously monitor the growth of intra- and extra-vesical iceballs during cryoablation, effectively avoiding peripheral bowel injury (24).

Doppler ultrasound is suitable in superficial cystic organs such as the bladder and allows real-time monitoring of intraoperative iceball growth (33,34). However, if gas is used to fill the bladder, it may obstruct the field of view and interfere with the operation.

CT is the most commonly used image-guidance device during tumor ablation. Injecting saline with iodine contrast into the bladder can not only improve visualization but also increase the contrast. The gas does not affect the sharpness of the CT images (35).

The bladder wall consists of mucosal, submucosal, detrusor, and plasma layers. MpMRI can differentiate between the inner and muscular layers of the bladder wall and determine the tumor infiltration depth (36). MRI has excellent diagnostic efficacy with higher resolution and contrast than CT and ultrasound (37). Multi-directional and multi-parameter imaging is engaged, which can accurately discern the size, morphology, location, and relationship with the surrounding tissues of bladder tumors. Due to its expensive equipment, longer scanning time, and the need for more sophisticated theoretical knowledge, MRI is less frequently used as a guiding device (38). Still, several studies have explored the value of biopsy and ablation in genitourinary tumors (39-41).

Exploration of combined treatment modalities for BC

Cryoablation is an ablative treatment based on extreme hypothermia. Ice crystal growth leads to cell membrane, organelle damage, and cell dehydration. Microthrombosis leads to ischemia of the tumor tissue. Apoptosis is induced by cryogenics, which stimulates immunity and produces a waterfall of ectopic tumor suppression. Cryoablation has some tumor immunity effects in addition to direct tumor-killing effects. It induces tumor cells necrosis and releases a variety of tumor antigens, which function as an autologous tumor vaccine and activate tumor-specific T-cell immunity. Cryoablation not only promotes the infiltration of T cells into the tumor, turning it into a hot-immune state, but also promotes the expansion of CD39⁺ tumor-specific T cells and reduces the proportion of bystander T cells (42). It changes the tumor microenvironment and the body’s immune status, generating an anti-tumor immune response, which can remove residual cancer cells in other locations (43).

Physiologically, programmed cell death 1 (PD-1) expression is initiated after T cell activation to prevent its overactivation. The upregulation of immune checkpoints (e.g., PD-1) is a compensatory mechanism after T-cell activation. However, most PD-1/programmed cell death ligand 1 (PD-L1) inhibitors benefit only 10–50% of patients (44,45). Many researchers have highlighted that cryoablation combined with a PD-1 inhibitor has a synergistic effect (46-50). T cells retain their antitumor properties even when the expression of PD-1 is upregulated. Combining cryoablation with PD-1 inhibitors can produce a potent and continuous antitumor effect. Therefore, it is necessary to explore combination treatment modalities.

In C57 mice (42), Mou et al. compared the size of the reimplanted tumors after cryoablation and surgical resection of subcutaneous primary tumors, concluding that the secondary tumors grew more slowly in the cryoablation group. A long-lasting antitumor immune response induced by cryoablation was achieved by enhancing antitumor immune memory and performing secondary immune surveillance. However, cryoablation produces a weaker immune effect and has a shorter duration of maintenance. Combining it with other therapeutic modalities may amplify and intensify this immune effect, resulting in better efficacy and longer survival.

Discussion

In genitourinary tumors, cryoablation has been widely used for kidney and prostate cancers. Partial nephrectomy (PN) and percutaneous ablation can be used to treat cT1 renal masses; cryoablation preserves postoperative renal function, without any evidence of differences in mid-/long-term follow-up compared to nephron-sparing surgery (51,52). In a solitary kidney setting, cryoablation has been associated with a lower risk of postoperative acute kidney injury (AKI) compared to PN. The functional outcome was comparable upon longer follow-up. The local recurrence rates were significantly higher in the cryoablation group with no significant difference in OS (53). In the research of Tan et al., whole gland cryoablation was shown to be potential a good option for men with localized prostate cancer who desire to preserve urinary continence and have an excellent oncologic outcome (54). Moreover, cryoablation could serve as a novel salvage treatment for locally recurrent prostate cancer (55).

Animal research has preliminarily assessed the safety of bladder cryoablation and confirmed the feasibility of cryoablation in healthy bladders. Devices used for guiding, cryoablation, and bladder protection media were evaluated (21-23). By monitoring the growth of the ice ball in real time, the cryoablation device allowed for predictable and effective cryoablation of the bladder. The bladder layer structures were completely necrotized while maintaining the integrity of the bladder. During recovery, the overall status of the animals was good (body weight, appetite, mobility, and energy levels remained normal), and no obvious abnormalities were indicated in the hemogram (19-23).

Cryoablation has been initially recognized for improving efficacy, controlling disease progression, and reducing disease recurrence. A multicenter randomized controlled study confirmed that cryoablation is also safe and effective in the treatment of NMIBC. Cryoablation after TURBT of NMIBC has superior local control rates, recurrence-free survival, and PFS compared to one-shot chemotherapy after TURBT (56). Furthermore, scholars have explored cryoablation’s safety and clinical efficacy in MIBC. Some studies have shown that cryoablation is effective in various circumstances (25-29). Cryoablation as an adjuvant therapy with TURBT is feasible and safe in T1–T2 MIBC. It is able to achieve satisfactory local control. In T3–T4 MIBC; cryoablation can serve as a palliative treatment to reduce the tumor burden, but needs to be combined with other treatments to improve the prognosis. Similarly, cryoablation has been examined for the treatment of small renal masses, with particular attention given to recurrence management, demonstrating the efficacy of active surveillance and re-ablation (57). In our center, we have also recommended cryoablation to lung cancer patients who were refractory to standard treatment or who presented with recurrence. Cryoablation is characterized as minimally invasive and repeatable. These approaches could also be considered in the context of BC to enhance post-treatment management and minimize long-term complications.

As research progresses, the understanding of the urinary microbiome’s role in BC offers new avenues for enhancing treatment protocols. For instance, findings by Nardelli et al. have identified Porphyromonas somerae as a potential biomarker for BC, detected through non-invasive urobiome analysis of first morning urine samples. This could pave the way for incorporating microbiome profiling into patient assessments before selecting cryoablation as a treatment strategy, potentially improving patient selection and treatment outcomes (58).

Adverse events that occurred in the studies were mild and manageable (25-29). During cryoablation, patients might experience symptoms such as lower abdominal and lower back pain, hematuria, and signs of urinary tract irritation. All complications should disappear completely after several weeks. Furthermore, serious adverse events can be significantly avoided by applying appropriate cryoablation devices (26), setting suitable parameters (27,28), and performing necessary organ protection (29). Thus, no operative-related deaths occurred in these studies and no bladder perforation, sexual dysfunction, or bladder fistula was reported.

Compared to traditional TURBT and radiotherapy, cryoablation offers several advantages. It is less invasive, has a mild impact on quality of life, and does not cause bone marrow suppression. BC patients, often elderly with multiple co-morbidities, may not tolerate general anesthesia. Cryoablation, requiring only local anesthesia, allows for precise treatment and in situ destruction (24). Its safety and efficacy have been demonstrated in various solid tumors. In the field of BC, cryoablation has been explored in numerous animal models, initially confirming its feasibility. However, in the real world, it is still in the exploratory stage of a few researchers. There is a lack of sufficiently convincing large-sample clinical trials, clinical guidelines, as well as clinical efficacy comparisons, and long-term prognostic analyses with established treatment options.

Due to the lack of relevant clinical guidelines and expert consensus, the parameters for cryoablation are mainly reliant on the operator’s experience. Different ablation devices, refrigerants, and parameters result in varying sizes of iceball volumes, tumor necrosis, procedural effectiveness, and safety, potentially impacting disease management and long-term prognosis. Cryoballoon refers to a balloon attached externally to the tip of the cryoprobe. It is cyclically filled with refrigerant to freeze and thaw the lesion, while the cryoprobe is filled with refrigerant inside the probe. Possibly, the cryoballoon may be more suitable for adjuvant treatment after TURBT (32). The cryoballoon can be embedded at the tumor base after filling. The cryoprobe is suitable for MIBC with extranodal growth and large tumor size. Liquid nitrogen can reach freezing temperatures of −190 ℃, whereas argon can reach −140 ℃. Liquid nitrogen is theoretically more efficient for freezing. Tumor necrosis is similarly affected by different freeze-thaw cycles and durations. In our clinical experience, there is a more pronounced degree of necrosis and cavitation within the tumor after 3 freeze-thaw cycles on lung tumors compared to 2 cycles.

Strengths of the review

This article analyzes recent research progress of cryoablation in MIBC from multiple perspectives, marking the first narrative review in this field. It summarizes animal models and clinical trials, focusing on various aspects of cryoablation equipment, parameters, monitoring devices, and organ protection techniques. Additionally, we have formulated and visualized future research blueprints. Cryoablation offers a novel treatment option for MIBC patients who are unsuitable for surgical resection or unwilling to undergo it, expanding the treatment protocols for BC.

Limitations

The article relies heavily on a limited number of studies, many from animal models. Cryoablation for MIBC is still in the exploratory stage. Firstly, in animal models, most of the studies have been performed on healthy bladders. Thus, it is necessary to develop a model of bladder tumor and validate it. Moreover, whether local fibrosis after cryoablation has an impact on bladder function or not remains unclear. Secondly, the clinical studies on cryoablation for MIBC have had small sample sizes and mainly focused on short-term outcomes. Additionally, there is no assessment of long-term outcomes and impact on genitourinary function. Thirdly, further clarity is required regarding the patients who will really experience significant clinical benefits. More robust clinical data, particularly from controlled trials, would be crucial to justify broader clinical adoption. Lastly, differences in cryoablation devices and refrigerants result in variable cryoablation parameters for MIBC.

Future perspectives

For solid organ tumors such as liver, lung, and kidney, temperatures of −140 or −196 ℃ are usually required to achieve tumor inactivation, but −40 ℃ is the lethal temperature for tumors. Thus, for bladder cavity organ tumors, the need for very low temperatures below −140 ℃ should be explored. For MIBC, clinical trials are necessary to further investigate the effectiveness and safety of various cryoablation devices and parameters.

MIBC originally required general anesthesia for TURBT and postoperative adjuvant radio-chemotherapy. Can transmural cryoablation be performed to destroy the main portion of the tumor, and then combined with local adjuvant therapy, such as cystic/internal iliac artery perfusion or intravesical perfusion chemotherapy, to consolidate the therapeutic effect? While achieving the therapeutic objectives, it enhances the patients’ treatment adherence, reduces the adverse effects, improves the patient’s quality of life after treatment, and thus improves the clinical management model of MIBC. In future, it will be necessary to sponsor multicenter, randomized controlled clinical trials to explore comprehensive protocols for MIBC and demonstrate their safety and long-term efficacy, such as cryoablation combined with systemic chemotherapy, cryoablation combined with bladder perfusion, cryoablation combined with arterial infusion chemotherapy, and cryoablation combined with intratumoural injections of chemotherapeutic agents.

Furthermore, clinical guidelines of cryoablation in MIBC should be made to further standardize the operation, which requires multidisciplinary collaboration between interventional radiologists, urologists, oncologists, and diagnostic radiologists.

Conclusions

Cryoablation for MIBC is a relatively safe, feasible, and promising minimally invasive treatment technique. The safety and effectiveness of cryoablation in T2–T4 MIBC have been preliminarily validated, demonstrating reliable short-term efficacy. Appropriate protective techniques can effectively prevent adverse events. However, the application of cryoablation in MIBC is still in the exploratory stage; there is an urgent need to conduct randomized controlled trials to further validate it adequately.

Acknowledgments

Funding: This study was supported by the National Key R&D Program of China (Nos. 2023YFC2414000 and 2023YFC2414004).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1174/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1174/coif). Both authors report that this work was funded by the National Key R&D Program of China (Nos. 2023YFC2414000 and 2023YFC2414004). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Board of Beijing Hospital (No. 2024BJYYEC-KY028-01) and informed consent was provided by all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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