- Цитотоксические механизмы термической абляции
- Роль диагностической биопсии для пациентов, направленных на термическую абляцию
- Отбор и подготовка пациентов
- Радиочастотная абляция
- Наблюдение и исходы теплового абляционного лечения
- Определение «успешности» операции
- Функциональные результаты
- Онкологические результаты
- Аблация для сохранения ранее леченных почек
- Будущее абляционного лечения
- Другие абляционные способы
- Термическая абляция как часть иммунотерапевтической стратегии
С ростом принятия частичной нефрэктомии за стандарт лечения небольших почечно-клеточных карцином (RCС) и подтверждение этого группами, подобными American Urological Association (AUA), все более часто используется нефрон-сохраняющая хирургия. Частичная нефрэктомия обеспечивает равноценный радикальной нефрэктомии канцерный контроль, но с дополнительным преимуществом сохранения почек, что дает важные отдаленные хорошие результаты. Однако некоторые пациенты с небольшими RCС, особенно пожилого возраста, с тяжелой почечной дисфункцией или с сопутствующей патологией, могут быть неподходящими кандидатами на хирургическое иссечение, но хорошими кандидатами на термическую абляцию — радиочастотную (RFA) или криоабляцию. Недавно опубликованные руководства AUA перечисляют абляционные методы как опции для лечения пациентов с небольшими новообразованиями почек.
Цитотоксические механизмы термической абляции
В RFA фрикции молекул воды, реагирующих на радиочастоты, вырабатывают тепло, которое разрушает опухолевую ткань. Световая микроскопия показывает самые ранние изменения почечной паренхимы в виде расплывчатости очертаний хроматина, повышенной цитоплазматической эозинофилии, утраты интеграции клеточной мембраны и интерстициальных геморрагий. Позже наблюдается обширный коагулирующий некроз с ранними инфильтратами фибробластов и острыми воспалительными элементами по границе RFA. Спустя неделю дегенерация ядер и острое воспаление становятся более явными. Клеточная смерть развивается в пределах нескольких минут экспозиции 50°C и выше. Температура в границах 50-100°C, поддерживаемая гомогенно в определенной области, является оптимальной для терапии. Более высокая температура может вызывать карбонизацию ткани с ограничением теплопроводности и, таким образом, снижать эффективность RFA.
Криоабляция непосредственно уничтожает опухолевые клетки, вызывая осмотическую дегидротацию, которая поражает энзиматические пути, органеллы и клеточную мембрану, и формирование внутриклеточного льда, которое переохлаждает цитоплазматическое содержимое.
Небольшие кровеносные сосуды повреждаются и спустя время закрываются тромбами, формируя гипоксическую микросреду опухоли и усиливая цитотоксичность. Четыре параметра предопределяют скорость клеточной цитотоксичности: быстрота охлаждения, достигнутая минимальная температура, продолжительность минимальной температуры и время оттаивания. Температура −40°C обязательна для достижения по всему объему опухоли; обычно это соответствует появлению льда за пределами опухоли на 0.5-1 см. Быстрое охлаждение и медленное размораживание также потенциируют цитотоксичность.
Роль диагностической биопсии для пациентов, направленных на термическую абляцию
Renal cell carcinoma. Clinical management. Eric A. Klein (Editor). Springer, 2013
With the increasing acceptance of partial nephrectomy as the standard of care for small renal cell carcinomas (RCCs), as well as its endorsement by groups such as the American Urological Association (AUA), nephron-sparing surgery will be increasingly employed. Partial nephrectomy has been shown to provide equivalent cancer control to that of radical nephrectomy, but with the additional advantage of renal preservation, which has important long-term health benefits. Nevertheless, there are some patients with small RCCs, particularly elderly patients, those with severe renal dysfunction, and those with competing comorbidities, who may be poor candidates for surgical excision. Many of these patients are good candidates for thermal ablation, either by radiofrequency ablation (RFA) or by cryoablation. Recently published AUA guidelines list ablative therapies as options for the management of patients with small renal masses.
Cytotoxic mechanisms of thermal ablation
In RFA, friction of water molecules reacting to radiofrequencies generates heat which destroys tumor tissue. Under light microscopy chromatin blurring, increased cytoplasmic eosinophilia, loss of cell membrane integrity, and interstitial hemorrhage are the earliest changes seen in renal parenchyma. Later, extensive coagulative necrosis with early infiltration of fibroblasts and acute inflammatory elements at the border of the RFA can be seen. Nuclear degeneration and acute inflammation becomes more pronounced after 1 week. Cell death occurs within minutes of exposure to temperatures at or above 50°C. Temperatures in the 50–100°C range are maintained homogeneously throughout the target area for optimal therapy. High temperatures (greater than 100°C) can actually compromise treatment because tissue carbonization occurs, which limits heat conduction and thus the efficacy of RFA.
Cryoablation directly kills tumor cells by causing osmotic dehydration that damages enzymatic pathways, organelles, and the cell membrane and by causing intracellular ice formation that supercools the cytoplasmic contents.
Small blood vessels are injured and in time become thrombotic resulting in a hypoxic tumor microenvironment that adds to the cytotoxicity. Four parameters determine the rate of cellular cytotoxicity: cooling rate, minimum temperature reached, time maintained at the minimum temperature, and thawing rate. A temperature of −40°C must be achieved throughout the tumor; this typically occurs when the ice ball extends 0.5–1 cm beyond the tumor margins. Faster cooling and slower thawing also improve cytotoxicity.
The role of diagnostic biopsy in patients undergoing thermal ablation
If a patient has a small renal mass suspected to be RCC and is a candidate for ablative therapy, a biopsy is performed for histologic confirmation of malignancy. At our institution, we perform these biopsies as a separate and preliminary step before deciding whether to pursue aggressive therapy, because a substantial number of tumors will prove to be benign and not require treatment. Thus, patients at high risk of complications with benign lesions are spared unnecessary procedures and anesthetics, as these have an indolent behavior that is unlikely to cause morbidity or shorten survival. The argument to not biopsy because of high non-diagnostic rates is no longer fully valid. The false-negative and non-diagnostic rates of percutaneous biopsy of renal masses have significantly improved in recent years as a result of improved techniques (such as core sampling in addition to fine-needle aspiration) and improved pathologic immunostaining panels. Patients confirmed to have RCC should be counseled about therapeutic alternatives, such as the reference standard of partial nephrectomy and the possible appropriateness of active surveillance.
In addition to pretreatment biopsies, in some cases postablation biopsies may be needed, as evidence suggests that imaging by itself may not be not sufficient to confirm treatment success in all cases, as outlined below.
Patient selection and preparation
The single most important requirement for the appropriate selection of patients for ablative therapy is the availability of good-quality imaging with a renal-protocol computed tomography (CT) or magnetic resonance imaging (MRI) examination. Thermal ablative treatments are all primarily guided by such imaging. The most ideal candidates for ablative therapy are patients with small (<3.5 cm) renal masses that are relatively exophytic and accessible percutaneously. In reality, many patients have variations of anatomy that present less ideal situations. Examples include tumors larger than 3.5 cm, tumors that are deeper and more central, and tumors in locations such as the anterior upper pole, which may be difficult to access percutaneously. In particular, larger tumors and deeper tumors have a lower success rate with ablative therapies, as has been shown in multiple studies. For example, Zagoria et al. showed that with each 1-cm increase in tumor diameter over 3.6 cm, the likelihood of recurrencefree survival decreased by a factor of 2.19. To enhance the effectiveness of ablation for larger tumors, some investigators have advocated embolization of the tumor prior to ablation. Renal angiography and selective embolization of the tumor-feeding arteries can reduce perfusionmediated cooling of the tissue (i.e., a heat-sink effect) during RFA, allowing a larger volume of tissue to attain a cytotoxic temperature.
Although tumor factors are important in determining the adequacy of an ablative therapy approach, patient-related factors are just as important and sometimes trump less than ideal indications for ablation. For example, we now often see patients who cannot be taken off anticoagulation agents, such as those with drug-eluting coronary stents; these patients have a very high risk of coronary thrombosis if the anticoagulants are acutely discontinued. Because ablative therapy minimizes the time off such compounds, it may represent the best form of treatment for these patients, even if they have less favorable tumor factors such as a central location or large size. Table 9.1 outlines our current indications for ablative therapy.
Table 9.1. Factors considered when evaluating patients for ablative therapy
- Tumor size: <3.5 cm most ideal
- Tumor depth: peripheral more favorable than central
- Tumor location: determination for percutaneous or laparoscopic access
- Elderly physiologic age or health status unfit for major surgery
- Major medical comorbidities or another primary malignancy that requires active therapy
- Enlargement of renal mass to 3 cm in size during active surveillance
- Need to minimize time off anticoagulation or antiplatelet compounds
- Prior ipsilateral partial nephrectomy or other major renal surgery
- Chronic kidney disease
The potential for complications still exists despite the minimally invasive nature of thermal ablative therapies. Also, given the lack of knowledge about the long-term results of these novel treatments, strict imaging surveillance is imperative for an indefinite period. Patients who are unable to meet these follow-up criteria—imaging surveillance and possible postablation biopsies— should not, in our opinion, be considered for ablative therapy.
Patients also must be medically cleared for delivery of general anesthesia. Although some centers perform ablative therapy with moderate sedation, our philosophy is that the likelihood for a single successful treatment depends on the ability to control respiratory excursion of the kidney, resulting in better targeting, and on allowing for treatment as long as is needed during the case. These two factors are critical for complete tumor ablation in a single procedure.
After a needle biopsy confirms malignant histology, patients are referred to an interventional radiologist to assess whether the tumor is accessible percutaneously under CT or MRI guidance. On occasion repositioning the patient in the prone or oblique-prone position will shift some of the structures such as the spleen or colon away from the zone of treatment, allowing percutaneous therapy. Other adjunctive maneuvers, described below, may also be performed to mobilize or protect structures from heat injury. Tumors that remain in a difficult location or close to bowel or the ureter may require a laparoscopic approach, which allows mobilization of these structures away from the tumor and the intended zone of ablation. In the laparoscopic approach, initial electrode placement is performed under laparoscopic ultrasound guidance.
Our RFA technique has been previously described. Briefly, percutaneous RFA is performed with the patient under general anesthesia in prone position. RFA is delivered using a 200 W impedance-based device. One or more electrodes (depending on tumor size) are positioned into the tumor under CT guidance, and sequential overlapping ablations are then performed, depending on the size and location of the tumor, until it is completely ablated, along with a margin of surrounding normal tissue. Some interventional radiologists withdraw the electrode into the subcutaneous tissues and ablate the tract, although it is not clear that this is required. In cases in which the tumor may remain adjacent to critical structures such as the intestine, nonionic fluid (5% dextrose in water or sterile water) may be injected and hydrodissection performed, allowing displacement of the critical structures away from the area of intense heat. Additional measures for protecting normal tissues from heat injury include irrigating cooled saline in a retrograde fashion through a ureteral catheter to protect the collecting system, rotating the RFA electrode to displace the kidney, and strategically placing an angioplasty balloon. Immediately after RFA treatment, contrast material is given intravenously to assess the ablation zone and confirm adequate treatment. Contrast-enhanced CT images taken immediately after ablation demonstrate a sharp boundary between the zone of ablation and the normal renal parenchyma. Mild, diffuse enhancement within the zone of ablation is expected with delayed images, but any nodular or crescent areas of intense enhancement are considered unablated (Fig. 9.1). Under these circumstances or when the margin of ablation is close to the tumor boundary, an RFA electrode can be placed directly into the area of concern, and an overlapping ablation can be performed. With this strategy, most renal tumors can be completely ablated in a single session.
Fig. 9.1. Computed tomography scan 1 month after RFA of a left renal mass showing an enhancing crescent shaped area of unablated tumor (arrows). Repeat ablation was guided by this imaging, specifically targeting these areas. Copyright S.F. Matin 2011
Tumors that require laparoscopic RFA (such as anterior or medial tumors or those close to the renal hilum or ureter) are treated using a transperitoneal laparoscopic approach. The patient is placed in modified flank position, and access is gained using a Veress needle. A standard threeport approach is performed; the colon is mobilized, as are other critical structures, such as the ureter, as dictated by tumor location, and the area around the tumor is exposed. The perinephric fat is mobilized, except that overlying the tumor, which may either be left in place or sent for pathologic evaluation to confirm the absence of fat invasion. Intraoperative ultrasonography is then performed to evaluate the location of the tumor and its depth. At this point, small cautery marks are placed on the renal capsule at the margin of intended treatment to serve as visual landmarks, as there will be significant shrinkage and distortion of anatomic landmarks during treatment. The RFA electrode is then placed into the tumor under ultrasound guidance until the tip is at the deepest tumor margin. This initial targeting is absolutely critical because visualization of this margin is most optimal before treatment. After RFA starts, the resulting vaporization and cavitation cause gas and microbubbles to form in the parenchyma, significantly degrading the ultrasound image and limiting accurate targeting. Once the deep margin is treated, the electrode is withdrawn partially and the process repeated. In addition to facilitating visualization, this maneuver actually achieves a vascular amputation of the more superficial untreated levels, such that the overlapping superficial ablations proceed more quickly. The electrode can also be repositioned as necessary into the more peripheral aspects of the zone of intended ablation, again treating from deepest to more superficial levels, until the entire tumor and margin are treated.
Cryoablation has been described using a variety of access methods, including open, laparoscopic, and percutaneous. The open approach is now largely historical, although there are occasional cases of multifocal disease in which open partial nephrectomy can be combined with thermal ablation of additional lesions to minimize the ischemic interval. The most common approach is laparoscopic, although an increasing number of publications report percutaneous route. The laparoscopic approach is similar to that described for RFA, with a notable exception: during cryoablation, laparoscopic ultrasound guidance is utilized throughout the entire treatment process. The ice-ball edge is seen in excellent detail as an advancing hyperechoic rim with postacoustic shadowing. This ability to monitor the treatment probably is cryoablation’s single greatest advantage. However, such monitoring requires significant mobilization of the kidney, because the postacoustic shadowing prevents visualization of the treatment edge opposite the ultrasound transducer. Therefore, the ultrasound probe needs to be navigated around the kidney at multiple locations in order to circumferentially visualize the advancing margin of treatment. This amount of renal mobilization and perinephric dissection is probably also the reason why surgical salvage of laparoscopic cases is rendered so difficult compared to salvage of percutaneous therapy, as discussed below.
Percutaneous cryoablation is also performed similarly to percutaneous RFA, as described above. Percutaneous cryoprobes are now smaller (17 gauge to 2.4 mm in diameter) than prior generation probes. As such, percutaneous cryoablation of most renal tumors requires strategic placement of more than one probe. A major advantage of percutaneous cryoablation over RFA is that growth of the ice ball can be carefully monitored using CT or MRI, allowing for optimal targeting. The ice ball appears as an area of low density on CT images, so the interface of the ice ball and the normal kidney is very well delineated. However, the boundary of the ice ball against the retroperitoneal fat, which also appears as low density on CT images, is less well defined. When percutaneous cryoablation is performed under MRI guidance, the ice ball can be imaged in multiple planes. It appears as an area of markedly low signal intensity on all pulse sequences (T1 or T2 weighted). Careful monitoring of the ice ball allows for modulation of cryogenic gases in different probes to prevent growth of the ice ball in one or more dimensions. This modulation provides an additional safety measure that is not possible with RFA. The inability to visualize beyond the advancing ice ball is the main reason that using solely ultrasound monitoring during percutaneous cryoablation cases is not recommended, as the medial (most inner) edges of the advancing ice ball cannot be adequately seen.
Whether cryoablation is done percutaneously or laparoscopically, two freeze/thaw cycles are performed, which optimizes tumor cytotoxicity. A margin of normal tissue of at least 0.5 cm beyond the tumor is treated; the ice-ball edge has been shown to represent a 0°C gradient, while 0.5 cm within the ball the temperature is −20°C, the minimum temperature required to achieve adequate tumor cytotoxicity. The recent availability of thinner probes allows placement of multiple probes for ablation of larger tumors. However, one concern is that the routine use of multiple probes may increase the risk of ice-ball related fracture, a complication unique to cryoablation that can predispose to significant hemorrhage during thawing. In fact, in a recent analysis by Vricella and colleagues, the only significant predictors of complications after cryoablation were the number of cryoprobes used and comorbidity index.
Follow-up and outcomes after thermal ablative therapy
Patients are seen 4–6 weeks after treatment for a renal-protocol CT or MRI examination, and if the initial imaging findings are favorable, patients return every 6 months for 2 years. After 2 years, depending on the findings of imaging and biopsy (if performed), semiannual, annual, or biannual follow-up is recommended. This follow-up schedule was recommended in a prior multiinstitutional study and consensus statement.
Confirmatory biopsies after ablation are generally not performed in the first 6 months, as data suggest that in some cases, particularly after RFA, tumor and cellular architecture is preserved, possibly leading to false-positive biopsy findings. A postablative biopsy is considered, however, after 6 months, for any enlarging lesions or when there is a concern regarding recurrence, as discussed below.
Treatment has traditionally been considered successful on the basis of two findings on imaging studies, absence of enhancement and involution of the tumor. However, there can be confusion when thermally ablated lesions, in the absence of enhancement, do not involute. This scenario, which is common, complicates the traditional definition of success. Matsumoto and colleagues described the natural radiological history of RFA-treated kidney tumors and showed that many tumors retained an appearance similar to that of the original tumor, but with absence of enhancement and involution. There are reports showing viable cancer cells on percutaneous biopsies of ablated lesions in the absence of contrast enhancement. As well, we have found that viable cancer cells are seen on biopsy in the absence of enhancement and tumor involution in approximately 8–10% of cases, at an average time of 23 months after ablation. These cases essentially represent false-negative imaging findings.
As well, the potential exists for false-positive imaging findings, wherein there appears to be recurrence and progression of tumor as noted by new enhancement, enlargement, and infiltrative changes around the zone of ablation. Biopsies or resection in some of these cases have shown inflammation but no viable tumor despite extensive sampling. It is unknown what causes these de novo massive inflammatory reactions that frequently, if observed over time, lead to significant involution of the ablation zone. Undoubtedly, however, these false-positive imaging scenarios complicate the clinical picture and can lead to unnecessary interventions or patient anxiety about cancer recurrence.
Biopsy samples should be obtained from any areas of nodular enhancement. In absence of any abnormal enhancement in the zone of ablation, a question arises as to the potential sampling bias of postablation biopsies. The zone of ablation is frequently larger initially than the original tumor because of treatment of a normal margin and, in some cases, tissue edema. Thus, needle biopsies, if not thoughtfully considered, may easily miss small foci of recurrence.
To address these concerns, our technique includes obtaining multi-quadrant core biopsy specimens (Fig. 9.2). A guide needle is inserted under CT or real-time CT fluoroscopic guidance into the center of the tumor. An automated, sidecutting core biopsy needle is inserted in coaxial fashion to obtain at least three biopsy samples. When the zone of ablation is large enough (at least 2 cm), the guide needle is then repositioned to obtain biopsy samples from the medial, lateral, superior, and inferior margins of the ablation zone. Samples from different areas of the ablation zone are labeled accordingly and submitted separately for pathologic analysis.
In general, ablative therapies appear to cause less renal dysfunction than do partial nephrectomy and radical nephrectomy, although the data are likely subject to retrospective and selection biases. Lucas and colleagues compared renal function using estimated glomerular filtration rates in patients who underwent RFA, partial nephrectomy, or radical nephrectomy. The investigators found that patients who underwent RFA maintained greater kidney function and were less likely to develop stage 3 chronic kidney disease than those who underwent partial nephrectomy or radical nephrectomy. In addition, Raman and colleagues evaluated patients with solitary kidneys and reported that those who underwent open partial nephrectomy with cold ischemia had a greater decline in kidney function than those who underwent RFA. Another report of patients with solitary kidneys by Weisbrod and colleagues showed a large cohort treated by cryoablation with minimal change in renal function. Jacobsohn et al. and Hoffmann et al., reporting on ablative therapy in patients with solitary kidneys, showed minimal reduction in kidney function in this high-risk cohort. While these retrospective reports may be biased by selection factors such as tumor size and tumor location, the weight of the data to date supports ablative therapy as a viable nephron-sparing approach.
It should be noted that there are significant differences among various studies with respect to definitions of local recurrence and the quality of reporting, complicating comparative analysis of this literature. This variability results from a multitude of limitations in the published literature.
Fig. 9.2. (a–c) Figures showing multisite-directed CT-guided biopsy using an automated, side-cutting core biopsy needle, in order to maximize sampling of the zone of ablation. Copyright S.F. Matin 2011
For example, diagnostic pretreatment biopsies were not performed in most studies; thus, as a substantial portion of renal tumors prove to be benign, reports of survival and recurrence may be skewed. Additionally, it appears that the natural history of small RCCs is generally toward an indolent pattern of growth, thus the short followup of these lesions after ablative therapy has little significance. Many investigators describe success as tumor eradication after a certain number of planned or unplanned treatments, and the published reports may not include this information. Variable definitions of success may also not clarify whether reported recurrences include recurrence within the zone of ablation, in a separate area of the kidney that was not treated, and/or in an extrarenal site. These limitations in the literature were categorically described in the recent meta-analysis conducted by the AUA guidelines panel.
The AUA meta-analysis provides the most current summary of outcomes of various treatments for the small renal mass, including ablative therapies. Cryoblation and RFA were associated with significantly lower local recurrence-free survival (local RFS) rates (87–91%) than were surgical treatments (³98%). This difference is made more pronounced by the fact that the follow-up period after ablative therapies was much shorter than that for open partial nephrectomy and other surgical treatments (median 18.2–19.4 months vs. 46.9 months for partial nephrectomy), suggesting that the local RFS rate seen after ablation may be even lower with longer follow-up. Metastatic RFS was high regardless of approach, but this finding may reflect the indolent nature of small renal tumors. This analysis provides valuable information that should be shared with patients during counseling.
Generally, complications related to ablation are secondary to local effects and less likely due to systemic adverse events. Pain, paresthesia, neuromuscular complications, pneumothorax, and other adverse events have been reported. For example, Johnson et al. documented morbidity rates in a multi-institutional study from four centers involving 271 patients . Complications were reported in 11.1% of patients, with the overwhelming majority of the complications classified as minor (9.2% of patients), largely consisting of pain or paresthesia at the site of probe insertion . A recent meta-analysis of the published data reported major non-urological complication incidence rates in the 3–7% range and major urological complication incidence rates in the 3–8% range. The rate of conversion to a more invasive or escalated procedure during cryoablation (3.5%) was nearly twice as high as during RFA (1.6%).
Bleeding is generally uncommon after RFA relative to cryoablation. Small hematomas may be seen during imaging but may not be clinically evident. Transfusion incidence rates are reported in the 1–5% range. Higher rates are seen with cryoablation, however, which is associated with the specific complication of ice-ball fracture as discussed previously. This complication may be caused by inadvertent torquing of the probe while the ice ball is formed, or possibly by the creation of larger cryolesions. The fracture may be hairline in size initially and not readily apparent during the freeze cycle, but during thawing, as vascularity is reestablished, sudden and significant hemorrhage can occur.
Fig. 9.3. Computed tomography scan 6 months after RFA of a right renal mass showing a small amount of urine extravasation into and around the zone of ablation. The patient was asymptomatic and observed. Copyright S.F. Matin 2011
Hematuria and clot obstruction can occur with treatment of a more central tumor, and in cases of solitary kidneys, this complication can result in acute renal failure, which may require stent placement. Concerns have been expressed about treatment of the urinary collecting system and formation of a urinary fistula, but animal and clinical evidence suggests that as long as the collecting system is not mechanically punctured, this adverse event is unlikely to result in a clinically meaningful adverse event. Rarely, we have incidentally seen wisps of urine tracking within or just outside the ablation zone (Fig. 9.3). These patients are monitored and treated conservatively, with nearly every case showing resolution over time. Tract seeding of a tumor is exceedingly rare and is generally avoided with careful technique.
Ablation for salvage of previously treated kidneys
Repeat surgery in patients who have had prior partial nephrectomy or other renal procedures is much more difficult. The retroperitoneal and perinephric desmoplastic reaction can add significantly to the complexity of the case. Repeat partial nephrectomy is associated with significant rates of blood loss and morbidity and with a quantifiably higher mortality rate in some series. In this setting, percutaneous ablative therapy may offer a viable, less morbid alternative to repeat partial nephrectomy, prompting some to recommend ablation as a primary option in those at high risk for reintervention, such as patients with von Hippel–Lindau syndrome.
A significant proportion of reported patients with a solitary kidney who are treated with ablative therapies had a prior partial nephrectomy. The results of such series indicate generally favorable outcomes despite the risks and challenges involved. For instance, Raman and colleagues published a multi-institutional study of patients with a solitary kidney treated with either partial nephrectomy or RFA; preservation of renal function favored RFA, possibly as a result of avoiding ischemic insults, although patient selection may have also contributed. Similarly, Weisbrod and colleagues reported on cryoablation in 31 patients with a solitary kidney—the majority of whom had had prior ipsilateral renal procedures—and showed a 92% local tumor control rate, 1 day hospitalization, and a 20% major complication rate. In comparison, one can evaluate outcomes after repeat partial nephrectomy to appreciate the context of these outcomes. Liu and colleagues reported their experience with 25 patients undergoing repeat partial nephrectomy in a solitary kidney, showing an average of 2,400 ml blood loss, 8.5 h mean operative time, and a 52% major complication rate, which included one (4%) death and a 12% rate of renal loss requiring long-term hemodialysis. Although the groups from these separate institutions likely have notable baseline differences, the dramatic difference in outcomes highlights the potentially important role of ablative therapy in the salvage setting, particularly if it can be delivered percutaneously.
However, surgical salvage of recurrence in previously ablated kidneys may also represent a surgical challenge. Nguyen et al. reported their experience with surgical salvage of RCC recurrence after thermal ablation, showing that cryoablation in particular can lead to extensive perinephric fibrosis, which can complicate or preclude attempted surgical salvage. Of ten patients in whom partial nephrectomy was attempted, only two were able to have it done, and in most cases a laparoscopic approach was not feasible. Kowalczyk and colleagues reported their experience with partial nephrectomy in 13 patients after RFA, with no cases converted to radical nephrectomy. The majority of patients had significant fibrosis present in the operative field, however, and operative times were long (7.8 h).
If one looks more critically at these studies, it appears that cases involving initial laparoscopic ablation, which were performed more frequently using cryoablation, are the ones in which the greatest difficulty is encountered and in which adverse events are most likely to occur. Cases treated percutaneously, which until recently were reported more frequently using RFA, are much easier to salvage, as the area of desmoplastic reaction is confined to the area of treatment and not throughout the entire perinephric space. To the point, when evaluating the data from Nguyen and colleagues, patients undergoing surgical salvage after RFA procedures (which were nearly all done percutaneously) had no intraoperative or postoperative complications, minimal blood loss, and no need for intraoperative blood transfusions.
The future of ablative therapies
Other ablative therapies
Nearly every promising energy source has been investigated for invasive and noninvasive ablation of small renal tumors, including laser thermoablation, photodynamic therapy, microwave thermotherapy, high-intensity focused ultrasound (HIFU), and robotic four-dimensional radiotherapy. To date, all these approaches have been associated with either: (1) technical challenges limiting their clinical application (e.g., laser, photodynamic therapy, microwaves); (2) inferior clinical outcomes (e.g., HIFU); or (3) only very preliminary experience that represents inadequate assessment of clinical potential (e.g., radiotherapy). Laser and microwave ablative therapy in particular have multiple parameters that have not been systematically studied, such as ideal wavelengths, power outputs, duration of treatment, or applicator size and type. Cryoablation and RFA thus remain the two most studied and clinically applied thermal ablative technologies to date.
Thermal ablation as part of an immunotherapeutic strategy
A novel aspect of thermal ablative therapy is its in situ treatment of malignancy, which not only destroys tissue but also initiates a local inflammatory cascade. Nonspecific inflammation has been linked as a key initial step in the development of specific immunologic events, such as rejection of transplanted organs and ischemia/ reperfusion injury. This potential ability of ablation to act as an in situ initiator of tumorspecific immune responses represents a potential new paradigm in the treatment of RCC and other cancers. Case reports after cryoablation and RFA document tumor regression after ablation, even in cases of biopsy-proven metastatic disease. In the majority of cases, however, such phenomena are not seen, leading to the conclusion that establishment of a nonspecific immune reaction may be insufficient by itself to trigger antitumor immune responses. There is therefore great interest in combining ablation with immune-modulating agents. This “combinatorial” therapy is yet to be investigated or clinically applied, but several investigators are actively researching this very interesting and novel aspect of ablation.
Thermal ablative therapy with RFA and cryoablation has gained a foothold in the armamentarium of treatments of the small renal mass. Rather than panacea, thermal ablation appears to be best suited for patients with difficult medical, anesthetic, or anatomic situations in whom the lower efficacy rates are balanced by the reduced risk of serious adverse events. Elderly patients with an enlarging mass, with extensive comorbidities, or those with a recurrence after prior partial nephrectomy represent situations where thermal ablation therapies may have their best roles. While newer energy modalities and delivery devices continue to be investigated, RFA and cryoablation continue to have the largest clinical experience and available data.