Cryoablation techniques in bladder cancer: A review

1 Bladder cancer

Bladder cancer (BC) ranks as the tenth most common cancer globally and climbs to seventh among males. The global age-standardized incidence rate (per 100,000 person-years) is 9.5 in men and 2.4 in women^[1]. Histopathologically, BC is broadly divided into urothelial and non-urothelial types, with squamous cell carcinoma (SCC) being the most common in the latter category. Urothelial carcinoma represents over > 90% of BC cases in Europe and North America, while SCC predominates in Middle Eastern regions where Schistosoma haematobium is endemic. Almost 80% of BC cases present as non-muscle invasive disease. Among these, 60% are confined to the bladder mucosa (pTa), 30% invade the submucosa (pT1), and 10% present as carcinoma in situ^[2,3,4]. Patients with non-muscle-invasive bladder cancer (NMIBC) have a higher prevalence due to longer survival times and a lower risk of cancer-specific mortality compared to those with muscle-invasive bladder cancer (MIBC)^[5-6]. The five-year survival rate for BC correlates with the disease stage at diagnosis, ranging as high as 95.8% for carcinoma in situ and as low as 4.6% for metastatic disease, underscoring the importance of accurate and timely diagnosis for the prognosis of BC patients^[7].

The standard treatment for diagnosing and managing NMIBC is transurethral resection of bladder tumors (TURBT)^[8-9]. While TURBT alone can completely remove NMIBC, recurrence and progression to muscle-invasive are common. Significant variation in the 3-month recurrence rate suggests incomplete TURBT or frequent recurrences in many patients^[10]. MIBC is an aggressive form requiring timely management. The current standard of care is neoadjuvant chemotherapy followed by radical cystectomy, an approach associated with significant morbidities. However, refinements in the chemotherapy regimens, perioperative care, and surgical techniques have led to improved overall toxicity profiles and faster recovery^[11,12,13]. The 5-year overall survival rate for patients undergoing radical cystectomy with locally advanced bladder cancer (pT_3-4N_–, or pN₊) is approximately 50%^[14]. Most local recurrences or distant metastases occur within 2 years after radical cystectomy^[15]. BC that progresses to metastasis is generally incurable and has a poor prognosis. Patients receiving platinum-based chemotherapy for metastatic disease have a median survival of 9-26 months^[16,17,18]. However, better outcomes (28%-33% survival at 5 years) have been observed in patients with oligometastatic disease treated with total metastatic tumor (TMT), including metastasectomy^[19-20]. Notably, bladder preservation in carefully selected patients can lead to acceptable oncological outcomes and better quality of life^[21,22,23]. Optimizing bladder preservation protocols and accurately identifying patients who tolerate and respond well to various treatment modalities will significantly enhance survival in the future^{[24,25,26,27,28,29,30,31]}.

Ablation therapy stands as one of the earliest and widely used minimally invasive treatment methods for cancer in various locations^[32]. Local ablation therapy encompasses thermal ablation and cryoablation, with this study focusing primarily on cryoablation technology. Cryoablation proves most effective for small tumors. Cryotherapy serves as a therapeutic tool for both benign and malignant diseases in organs such as the kidney, prostate gland, lung, liver, and breast. It is particularly useful for unresectable tumors, offering less trauma, quick recovery, good tolerability, and effective symptom control^{[33,34,35,36]}. This study reviews research advancements in cryoablation for bladder cancer.

2 Cryoablation

Cryoablation therapy, also known as cryotherapy, is a medical procedure that employs extremely low temperatures to destroy diseased tissue. This technique is primarily utilized for treating certain cancers, including those of the liver, kidney, prostate, as well as both benign and malignant skin tumors^{[37,38,39,40]}.

Cryoablation operates on the Joule-Thompson principle, a concept in physics first applied in 1993 to induce cell death through cold exposure^[32]. Typically conducted under the guidance of imaging techniques such as ultrasound or CT scans, this procedure involves inserting one or more slender probes (cryoprobes) into the targeted cancer or tissue. Liquid nitrogen or argon gas circulates through the probes, freezing the tissue and forming ice balls that destroy the cells. The formation of these “ice balls" is monitored in real-time using CT scans during multiple freezing and thawing cycles, which is a unique advantage in treating nonaerated organs^[41-42]. Multiple cycles and several probes may be employed for larger tumors to ensure full ablation^[43]. Cryotherapy destroys cells by extracting heat, utilizing methods like liquid nitrogen or pressurized argon gas, both of which reach temperatures around -185°C. The key to cryotherapy is low temperatures. All cells, except those prepared for cryopreservation, are destroyed at temperatures around -40°C^[33]. Cytotoxic ice temperatures have been observed around 4-5 mm within the ice ball’s perimeter^[44-45].

The advantages of this treatment include less trauma, faster recovery, and fewer side effects compared to traditional surgery. Typically minimally invasive, it can be done under local anesthesia, reducing the patient’s hospital stay and recovery time. Vasoconstriction around the frozen area may also reduce the risk of bleeding during treatment. Post-treatment symptoms, like pain, swelling, fever, and other reactions, are generally mild and resolve with symptomatic treatment^{[46,47,48,49,50]}.

However, cryoablation has its limitations. It may not work for all types of cancer, especially cases that have metastasized widely. The treatment’s efficacy may be affected by the size and location of the tumor, with larger tumors, tumors near significant blood vessels, and tumors in vital organs posing challenges for complete ablation^[51]. Additionally, there is a risk of tumor recurrence in the treated area^[52]. Therefore, cryoablation is more suitable for early malignant tumors with small size and moderate location.

In summary, the key factors in cryoablation are freezing temperature, speed, and duration^[33]. Cryotherapy is mainly performed percutaneously with minimal harm and no absolute contraindications. This makes it an effective complementary treatment for patients unsuitable for surgery, aiding in tumor control or managing oligometastatic disease. The decision depends on the specific cancer characteristics, the tumor’s location, and the patient’s overall health.

3 Cryoablation in the treatment of bladder cancer

Bladder cancer, a common malignant tumor of the urinary system, is treated through various methods including surgery, systemic medicine therapy, radiotherapy. In recent years, advancements in medical technology have introduced cryoablation therapy as a novel method for treating early bladder cancer (Fig. 1). This minimally invasive approach offers precision and rapid recovery, presenting a new treatment option for patients.

Fig. 1

Strategy for choosing cryoablation treatment for bladder cancer

Prior to cryoablation, a thorough cystoscopy is essential to assess tumor size, location, and quantity, guiding the selection of the type of cryoprobe and treatment plan. During the procedure, patients are typically under general anesthesia. A cryoablation probe is placed into the tumor tissue via cystoscopy. Post-treatment symptoms such as poor urination and bladder irritation are common, requiring dietary adjustments and pharmacological intervention^{[53,54,55,56]}.

Cryoablation has been a supplementary treatment option for BC for over seventy years. McDonald et al. explored cryoablation’s impact on bladder cancer in dogs in 1950, noting the formation of characteristic necrotic lesions^[57]. Permpongkosol et al. demonstrated the morphological changes from percutaneous full-thickness bladder cryoablation in pigs, confirming reliable tissue destruction without bladder perforation. The initial data indicated feasibility and safety of trials in treating bladder tumors using cystoscopic, laparoscopic, or image-guided techniques in 2006^[58]. At the same time, it showed controllable transmural necrosis in both single and repeated cycles without bladder perforations^[58]. Nevertheless, there is limited evidence regarding the use of cryotherapy in treating intraluminal tumors, such as bladder cancer, whether metastatic, MIBC, or NMIBC^[59]. Factors potentially hindering its clinical implementation include clear ice ball visibility on CT scans, precise coverage matching complete necrosis, and preventing damage to bladder, prostate, and uterine structures^[58,60-61]. Existing reports are scattered and primarily consist of case reports^[62-63], and a limited amount of clinical data^[64,65,66].

One feasibility study reported the success of CT imaging–guided percutaneous argon-helium cryotherapy in treating 32 patients with MIBC^[64]. All patients had clinical stage T_2-4aN₀M₀. Bladder cryoablation was technically successful in all 32 cases, and 30 cases required only one treatment session.

No major complications were observed, and bladder integrity was maintained in all patients. This study provides preliminary evidence suggesting that this minimally invasive method for ablating bladder tumors using CT imaging-guided percutaneous argon-helium cryoablation is promising and safe for treating patients with muscle-invasive bladder cancer^[64].

Cryoablation may also be a practical option for metastatic bladder cancer. A retrospective study involving 23 patients who underwent comprehensive cryosurgery for metastatic bladder cancer showed a progression-free survival (PFS) of 14 ± 8 months over four years of follow-up. The study suggested outcomes surpassing those for platinum-based chemotherapy, with differentiation status and tumor size influencing the efficacy of percutaneous cryoablation. However, tumor location and histopathology had no effect on PFS^[65].

Cryoablation is a therapeutic approach that employs extreme cold to induce necrosis and apoptosis in living cells^[67]. The necrosis caused by extreme cold has the potential to trigger a systemic anti-tumor immune response by releasing tumor antigens. This implies that cryoablation might serve as an autologous tumor vaccine^[68-69]. Recently, there have been changes in preferred medications, yet there have been limited advancements in the domain of medical devices for bladder cancer. Endoscopic balloon cryoablation (EBCA) showed a promising minimally invasive technique for intraluminal cancer. EBCA is presently being assessed as an innovative option for treating bladder cancer^[66].

There is a prospective randomized clinical trial (RCT) that involves combining cryotherapy with the standard transurethral resection (TUR) for patients with bladder cancer. This study is the first to demonstrate that EBCA is a safe and effective adjuvant therapy when used alongside TUR for NMIBC. The cryoballoon, which uses liquid nitrogen, was specifically designed for use under a cystoscope and resectoscope. The feasibility and safety of using cryoablation for bladder tumors were confirmed through experiments on animal models and a small, single-arm preclinical trial before^[70-71]. Subsequent research has revealed that the tumor-specific immune responses induced by cryoablation could reduce tumor recurrence and metastasis^[59].

4 Conclusion

Cryoablation is a minimally invasive surgical procedure offering notable advantages for localized tumor control compared to traditional surgery or systemic drug treatments. While randomized studies remain limited, increasing evidence suggests its potential application in bladder cancer management, particularly when combined with transurethral resection (TURBT) or pharmacological therapies.

Currently, cryoablation is not a standard therapy for bladder cancer. Treatment decisions need to be discussed by a multidisciplinary team of urologists, oncologists, and interventional specialists. There is a pressing need for more randomized controlled trials to define precise patient selection criteria and treatment approaches.