**2. Cryoablation**

#### **2.1. Mode of action**

The therapeutic principle of cryotherapy treatment is selective destruction of tumour cells with minimal injury to the surrounding tissue. Argon and helium are the most commonly used freezing agents. New cryotherapy systems use the Joule-Thomson principle to generate lethal temperature down to −187.5°C. Very low temperature causes direct cellular damage during freezing phase and indirect reperfusion injury during the thawing phase.

Cellular changes secondary to cryotherapy treatment could be summarised in four main stages:


To achieve the described cellular changes, it is essential to achieve the following aspects of the cryotherapy treatment [7].

#### *2.1.1. Target treatment temperature*

It is understood that irreversible tissue damage is achieved when cells are exposed to temperature between −20 and −50°C. Different structures of the kidney react differently to freezing temperatures. This behaviour is largely related to collagen and elastin content. Renal collecting system and renal vasculature tolerate cryoablation without real long term injuries. However, renal parenchyma is usually destroyed at −19.4°C. It is recommended to achieve temperature of −40°C or below to ensure killing tumour cells. Thermosensors are usually placed at the edge of the tumour to ensure adequate treatment temperature for the area of interest.

#### *2.1.2. Double freeze-thaw cycle*

The standard of care during renal tumour cryoablation is double freeze-thaw cycle. This concept has been established after an experiment on 16 female dogs. More adequate area of treatment and liquefaction was achieved following two freeze-thaw cycles compared to dogs who had only one treatment cycle.

#### *2.1.3. Satisfactory ablation area*

Focal ablative treatment offers flexibility with treatment's approach. Tumours could be treated laparoscopically, percutaneously or less often open approach. The American Urological Association recommends percutaneous access over surgical approach whenever is feasible [8]. Focal ablative therapy is well tolerated and technically less challenging. Hilar dissection and clamping is not a prerequisite in focal ablative therapy. Renal parenchymal loss is minimal

The therapeutic principle of cryotherapy treatment is selective destruction of tumour cells with minimal injury to the surrounding tissue. Argon and helium are the most commonly used freezing agents. New cryotherapy systems use the Joule-Thomson principle to generate lethal temperature down to −187.5°C. Very low temperature causes direct cellular damage

Cellular changes secondary to cryotherapy treatment could be summarised in four main

• Formation of extracellular ice crystals leading to hyperosmolar extracellular environment

To achieve the described cellular changes, it is essential to achieve the following aspects of the

It is understood that irreversible tissue damage is achieved when cells are exposed to temperature between −20 and −50°C. Different structures of the kidney react differently to freezing temperatures. This behaviour is largely related to collagen and elastin content. Renal collecting system and renal vasculature tolerate cryoablation without real long term injuries. However, renal parenchyma is usually destroyed at −19.4°C. It is recommended to achieve temperature of −40°C or below to ensure killing tumour cells. Thermosensors are usually placed at the

The standard of care during renal tumour cryoablation is double freeze-thaw cycle. This concept has been established after an experiment on 16 female dogs. More adequate area of

edge of the tumour to ensure adequate treatment temperature for the area of interest.

during freezing phase and indirect reperfusion injury during the thawing phase.

• Formation if intracellular ice crystals causing cells damage

• Thrombosis and micro capillary damage leading to necrosis

following ablative therapy.

**2. Cryoablation**

212 Evolving Trends in Kidney Cancer

**2.1. Mode of action**

and cells shrinkage

cryotherapy treatment [7].

*2.1.1. Target treatment temperature*

*2.1.2. Double freeze-thaw cycle*

• Metabolic activity stops at −40°C

stages:

It is recommended to perform cryoablation treatment for renal tumours under real-time imaging. The operator should aim for treatment area of 10 mm beyond the margin of tumour to ensure adequate treatment temperatures.

#### *2.1.4. Duration of treatment*

The duration of treatment should be balanced against risk of suboptimal treatment with short cycles or risk of tissue fracture and bleeding with long treatment. The optimal duration of freezing cycles is not well described in the literature. Two active cycles with initial freeze cycle of 8–10 min and a second freeze cycle of 6–8 min is considered the optimal.

#### **2.2. Guidelines**

The European Association of Urology guidelines state that, due to lack of high quality data, no recommendation can be made on cryoablation and radiofrequency ablation [9]. The American Urological Association (AUA) recently released its guidelines for management of patients diagnosed with small renal masses [8]. Focal ablative therapy should be offered as an option rather than standard treatment in high risk patients [8, 9].

Cryotherapy treatment offers a viable alternative to surgery especially in following clinical circumstances:


Cryotherapy is usually recommended for small renal tumours (<3 cm in size). Cystic renal masses and hilar masses represent relative contraindications for cryotherapy treatment. Untreated coagulopathy is an absolute contraindication for cryotherapy treatment.

#### **2.3. Modality of treatment**

Cryotherapy treatment can be delivered percutaneously, laparoscopically or less often with open surgical approach.

Laparoscopic mobilisation of the kidney and accurate dissection of the tumour might provide an excellent exposure of the tumour. It allows treating anteriorly located tumours safely, thus avoiding injury to surrounding structures. Laparoscopic approach allows real time monitoring of ice-ball formation in cryotherapy treatment and confirmation of probes positioning.

Location of the tumour and surgical expertise would normally mandate the approach of laparoscopic cryoablation (transperitoneal or retroperitoneal). Standard three ports technique is used. Gerota fascia is incised. The kidney is mobilised and tumour is identified. The overlaying and surrounding fat might be excised to allow accurate assessment during the treatment. Histological confirmation with 18-gauge biopsy needle is advocated if no prior biopsies have been taken.

**2.5. Treatment outcomes**

ber of patients [10].

83.2 and 64.4% [13].

**2.6. Complications**

reported at 2.6%.

instantaneous cellular death.

tions following cryotherapy is 4.9% (3.3–7.4%).

**3. High temperature ablative techniques**

Currently, there are no RCTs comparing treatment outcomes of PN with focal ablative therapies for small renal masses. The CONSERVE trial was a feasibility multicentre RCT attempted to compare PN with CA and RFA. The study was however unable to recruit the desired num-

Focal Therapy in Kidney Cancer

215

http://dx.doi.org/10.5772/intechopen.85819

Rai and colleagues [11] performed recent meta-analysis in which they compared outcomes of partial nephrectomy and cryoablation. This study highlighted significantly lower recurrences rates following RAPN. The overall recurrence rates in the CA cohort were 11.5% compared with 0% in the RAPN cohort. Similar results were concluded from met analysis of 13 studies comparing laparoscopic and RAPN with LCA; 9.4 vs. 0.4% respectively [12]. The analysis suggested LCA might be associated with improved peri-operative outcomes. These meta-analyses found that impact on oncological survival and mortality outcomes was profound. These results should be carefully evaluated, as it might reflect the short oncological follow-up [11, 12]. A retrospective review of more than 800 patients reviewed the intermediate oncological outcomes of LCA. The 5 and 10 year disease survival was reported at 90.4 and 80.0% respectively; however the 5- and 10-year overall survival in the study was

Cryotherapy is relatively safe procedure with low risk profile. Percutaneous and laparoscopic cryotherapy have similar overall complication rates [14, 15]. As one might expect, the length of in hospital stay following percutaneous cryoablation is shorter when compared to laparoscopic cryoablation [15, 16]. A recent systematic review reported the overall rates of complications following cryoablation therapy range from 7.8 to 20%. Zargar and colleagues [17] found that complications rate for percutaneous cryoablation are lower than laparoscopic cryoablation (2.8–12.9% vs. 15–20% respectively). The incidence of major urological complica-

Post-operative haemorrhage is the common reported complication. Other reported complications are ureteric injury and obstruction, peri-renal abscess and haematuria. Other minor non-urological complications include pain and paraesthesia at the probe site, urinary tract infections and self-limited haematuria. Reintervention following cryoablation therapy is

Cancer cells are very sensitive to both very high and low temperature. Radiofrequency and microwave energies use the concept of high temperature (above 55°C). Thermal ablation causes denaturation of cellular proteins and vascular necrosis of tumour cells resulting in

Cryoprobes are inserted percutaneously under direct vision. Laparoscopic ultrasonography is used to confirm the location of the probes and the margins of the tumour. Treatment is delivered with double freeze-thaw cycle. Cryoprobes are removed. Low pressure check is performed to check for any post-interventional bleeding.

Percutaneous cryotherapy can be performed as an outpatient procedure under conscious sedation or general anaesthesia. It might offer an advantage to laparoscopic approach especially patients requiring multiple procedures as in Von Hippel-Lindau (VHL) disease. The American Urological Association (AUA) recommends a renal biopsy prior to ablation to provide pathological diagnosis and minimise over treatment of benign conditions [8].

Following anaesthetic induction patient is positioned in the prone or flank position. Lesion is characterised following the administration of intravenous contrast depending on imaging technique (iodinated or gadolinium contrast). Tumour is localised with finder needle (20 gauge). A representative biopsy is taken with 18-gauge Try-Cut core biopsy needle under CT/MRI guidance. Positioning of cryoprobes and prongs are confirmed with repeat imaging. Cryotherapy treatment is carried out achieving the standard of care principles. Once treatment is completed; cryoprobes are removed. Post treatment imaging is performed to check treatment adequacy and evaluate for potential bleeding.

#### **2.4. Follow-up and oncological outcomes**

The absence of histological evidence for treatment success remains an inherent criticism for focal ablative therapy. The interpretation of a routine biopsy following cryotherapy treatment is highly controversial. Therefore, the determination of treatment success is solely reliant on radiological evaluation. Radiological evaluation of treatment success is interpreted by complete loss of contrast enactment of follow-up CT or MRI scan. Treated renal lesion is expected to shrink by >50% in size within the first year following cryotherapy treatment. Most of urological institutions recommend first CT scan or MRI scan with 3–6 months post cryotherapy treatment. Currently, there is no consensus on surveillance after RCC treatment. A six monthly CT scan is usually recommended within the first year of follow-up. Annual CT scan is recommended thereafter if favourable response to treatment has been established.

Selective post cryotherapy treatment biopsy should be sought in the following situations:


#### **2.5. Treatment outcomes**

Location of the tumour and surgical expertise would normally mandate the approach of laparoscopic cryoablation (transperitoneal or retroperitoneal). Standard three ports technique is used. Gerota fascia is incised. The kidney is mobilised and tumour is identified. The overlaying and surrounding fat might be excised to allow accurate assessment during the treatment. Histological confirmation with 18-gauge biopsy needle is advocated if no prior biopsies have been taken.

Cryoprobes are inserted percutaneously under direct vision. Laparoscopic ultrasonography is used to confirm the location of the probes and the margins of the tumour. Treatment is delivered with double freeze-thaw cycle. Cryoprobes are removed. Low pressure check is

Percutaneous cryotherapy can be performed as an outpatient procedure under conscious sedation or general anaesthesia. It might offer an advantage to laparoscopic approach especially patients requiring multiple procedures as in Von Hippel-Lindau (VHL) disease. The American Urological Association (AUA) recommends a renal biopsy prior to ablation to pro-

Following anaesthetic induction patient is positioned in the prone or flank position. Lesion is characterised following the administration of intravenous contrast depending on imaging technique (iodinated or gadolinium contrast). Tumour is localised with finder needle (20 gauge). A representative biopsy is taken with 18-gauge Try-Cut core biopsy needle under CT/MRI guidance. Positioning of cryoprobes and prongs are confirmed with repeat imaging. Cryotherapy treatment is carried out achieving the standard of care principles. Once treatment is completed; cryoprobes are removed. Post treatment imaging is performed to check

The absence of histological evidence for treatment success remains an inherent criticism for focal ablative therapy. The interpretation of a routine biopsy following cryotherapy treatment is highly controversial. Therefore, the determination of treatment success is solely reliant on radiological evaluation. Radiological evaluation of treatment success is interpreted by complete loss of contrast enactment of follow-up CT or MRI scan. Treated renal lesion is expected to shrink by >50% in size within the first year following cryotherapy treatment. Most of urological institutions recommend first CT scan or MRI scan with 3–6 months post cryotherapy treatment. Currently, there is no consensus on surveillance after RCC treatment. A six monthly CT scan is usually recommended within the first year of follow-up. Annual CT scan is recommended thereafter if favourable response to treatment has been established.

Selective post cryotherapy treatment biopsy should be sought in the following situations:

• If a lesion demonstrates persistent contrast enhancement following treatment (Incomplete

• If a lesion demonstrates enlargement following cryotherapy treatment and or new contrast

vide pathological diagnosis and minimise over treatment of benign conditions [8].

performed to check for any post-interventional bleeding.

214 Evolving Trends in Kidney Cancer

treatment adequacy and evaluate for potential bleeding.

enhancement (Local tumour recurrence or progression).

**2.4. Follow-up and oncological outcomes**

treatment).

Currently, there are no RCTs comparing treatment outcomes of PN with focal ablative therapies for small renal masses. The CONSERVE trial was a feasibility multicentre RCT attempted to compare PN with CA and RFA. The study was however unable to recruit the desired number of patients [10].

Rai and colleagues [11] performed recent meta-analysis in which they compared outcomes of partial nephrectomy and cryoablation. This study highlighted significantly lower recurrences rates following RAPN. The overall recurrence rates in the CA cohort were 11.5% compared with 0% in the RAPN cohort. Similar results were concluded from met analysis of 13 studies comparing laparoscopic and RAPN with LCA; 9.4 vs. 0.4% respectively [12]. The analysis suggested LCA might be associated with improved peri-operative outcomes. These meta-analyses found that impact on oncological survival and mortality outcomes was profound. These results should be carefully evaluated, as it might reflect the short oncological follow-up [11, 12]. A retrospective review of more than 800 patients reviewed the intermediate oncological outcomes of LCA. The 5 and 10 year disease survival was reported at 90.4 and 80.0% respectively; however the 5- and 10-year overall survival in the study was 83.2 and 64.4% [13].

#### **2.6. Complications**

Cryotherapy is relatively safe procedure with low risk profile. Percutaneous and laparoscopic cryotherapy have similar overall complication rates [14, 15]. As one might expect, the length of in hospital stay following percutaneous cryoablation is shorter when compared to laparoscopic cryoablation [15, 16]. A recent systematic review reported the overall rates of complications following cryoablation therapy range from 7.8 to 20%. Zargar and colleagues [17] found that complications rate for percutaneous cryoablation are lower than laparoscopic cryoablation (2.8–12.9% vs. 15–20% respectively). The incidence of major urological complications following cryotherapy is 4.9% (3.3–7.4%).

Post-operative haemorrhage is the common reported complication. Other reported complications are ureteric injury and obstruction, peri-renal abscess and haematuria. Other minor non-urological complications include pain and paraesthesia at the probe site, urinary tract infections and self-limited haematuria. Reintervention following cryoablation therapy is reported at 2.6%.
