Defining the position of cryoablation in the therapeutic armamentarium of small renal masses

P.W.T. Beemster

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This thesis describes four aspects of renal cryoablation: (1) the in vitro and in vivo performance of the cryoprobes, (2) the histopathological diagnosis of the renal masses treated by cryotherapy based on intraoperative biopsy results, (3) the clinical outcomes of renal cryoablation in terms of perioperative complications, intermediate oncological and functional results and QoL, and (4) radiological follow-up. 1. Cryoprobe performance In renal cryosurgery one or multiple cryoprobes are used to destroy the tumour during two freeze cycles. It is critically important that each of these cryoprobes deliver a constant and predictable performance during each freeze cycle, so that the physician is sure the entire tumour is ablated. In chapter 2 we tested the performance of 17G cryoprobes and thermosensors in vitro. Cryoprobe performance was defined as the time it takes one cryoprobe to lower the temperature from 0 to -20° Celsius as measured by four thermosensors each at 3mm distance from the cryoprobe. It enabled us to analyse both measuring variations of the thermosensors and freezing variations of the cryoprobes; both between different cryoprobes and between different freeze cycles of individual cryoprobes. To investigate the influence of the freezing medium on performance, the cryoprobes were tested in two mediums: agar and gel. Furthermore, cryoprobe performance in gel was measured using more accurate ‘bare’ thermosensors, since the metal casings of the thermosensors may also influence temperature measurements. Lastly, since in the clinical setup 17G cryoprobes are used in a multiprobe configuration, they were also tested in such a setup. Our results show that one cryoprobe will deliver a reproducible performance during each freeze cycle. However, between different cryoprobes there is a statistically significant variation in performance, both in agar and gel. The mean performance in gel was 1.8 times faster in gel than in agar. In both mediums there was a significant difference between the four thermosensors in measuring cryoprobe performance. Mean cryoprobe performance in gel as measured by two bare thermosensors was a factor 2.7 faster compared to the performance measurements by regular thermosensors. In a multiprobe configuration, overall performance is less variable and more reproducible compared to a single cryoprobe. In conclusion, the performance of cryoprobes differs depending on the medium and measuring device used. Individual cryoprobes deliver reproducible freeze cycles. Although there is a statistically significant variation between the performances of different cryoprobes, most probably this does not affect clinical effectiveness. Moreover, in a multiprobe configuration performance between cryoprobes is less variable. In chapter 3 we aimed to identify clinical parameters or factors that may influence the freeze rate of cryoprobes in a multiprobe setup. To fulfil this objective we analyzed the procedural data of the first 70 cryoablations of renal tumours in 67 patients. Based on the intraoperative biopsy result, two groups were identified: those with biopsy proven renal-cell carcinoma (RCC) or undetermined (non-diagnostic) biopsy and those with benign masses. We calculated the intraoperative freeze rate in both groups and compared them. Finally, we performed a univariate and multivariate analysis to identify clinical parameters that signi¿cantly in¿uenced freeze rate. The following variables were analyzed: patients age, gender, and American Society of Anaesthesiologists (ASA) score, preoperative creatinine level, the presence of cardiopathy, hypertension, diabetes mellitus, or chronic obstructive pulmonary disease (COPD), the use of anticoagulants, the location of the tumour (right/ left kidney, and upper/middle/lower pole), and tumour size. Of the 56 procedures that met the inclusion criteria, 48 were included in the RCC group (39 RCC and 9 lesions non-diagnostic on histopathology) and 8 in the benign group. There was no statistically significant difference between the freeze rates of the two groups. In the univariate analysis preoperative creatinine levels >120 µmol/L, ASA score 3, diabetes mellitus, and the location of the tumour in the lower pole significantly increase freeze rate. Freeze rate was only lowered by the presence of COPD. In the multivariate analysis, the presence of diabetes mellitus and the location of the tumour in the lower pole were the only independent predictors for an increased freeze rate. In conclusion, freeze rate can be negatively or positively influenced by patient and tumour characteristics. Whether this also has consequences for oncological outcome has to be further examined. 2. Histopathological diagnosis based on intraoperative tumour biopsy Since in renal cryosurgery the tumour is ablated in situ there is no surgical specimen for pathological examination and therefore the histopathological diagnosis relies exclusively on biopsies. A considerable number of small renal masses are benign, so accurate diagnosis has important prognostic and follow up implications. Unfortunately, approximately 20% of core biopsies are non-diagnostic, i.e. the pathologist cannot make a diagnosis due to an insufficient amount of tissue or erroneous sampling of necrotic/fibrotic or normal renal tissue. In chapter 4 we investigated whether there are certain tumour and/or biopsy characteristics that can predict biopsy outcome. From 100 tumours <4.5cm in 94 patients intraoperative biopsies were obtained before cryoablation. The following parameters were statistically evaluated for predicting biopsy outcome: tumour size, location and exophytic part of the tumour, presence of nonenhancing areas inside the tumour (indicative of necrosis) on CT/MRI, size of the biopsy needle, the number of biopsies taken, and the quality of the biopsies. Twenty-two percent of biopsies were non-diagnostic. There were no significant differences in parameters between the diagnostic and non-diagnostic group. There was a positive correlation between tumour size and number of biopsies, and between the presence of non-enhancing areas and both biopsy needle size and number of biopsies taken. The conclusions that can be drawn from this study are that in real life and in the absence of a protocol determining a fixed number of biopsies per tumour, more biopsies are taken from larger tumours, and that larger tumours contain more non-enhancing areas indicative of necrosis. However, since none of the parameters were correlated to a non-diagnostic biopsy, the rate of non diagnostic biopsies is most likely inherent to the difficulties encountered in sampling small renal masses. The intraoperative biopsies taken during laparoscopic renal cryoablation are obtained from the tumour just prior to the actual ablation. This can have some negative side effects for the procedure. For example, the bleeding that occurs after taking a biopsy may interfere with the correct placement of the cryoprobes, and the puncture site could be a point of origin of a capsular tear or tumour fracture after ablation. At least hypothetically it can also lead to needle-tract seeding. In chapter 5 we investigated whether taking the biopsies straight after the ablation (so effectively taking biopsies of the frozen tumour) could lower complication rate without influencing the ability of pathologists to make a correct diagnosis. To investigate this we took both pre- and postcryoablation 18 Gauge biopsies of 21 renal tumours in 20 patients. They were processed separately and firstly evaluated simultaneously by the institutional uropathologists. Secondly, the randomly arranged slides of the preand postcryoablation biopsies were evaluated by two other uropathologists who were blinded to the moment of biopsy taking. They were asked to give the histopathological diagnosis and whether they thought the biopsies were taken pre- or postcryoablation. Evaluation included tumour subtyping and assessing Fuhrman grade in case of clear cell or papillary subtype RCC. The diagnostic yield of the pre- and postcryoablation biopsies and interobserver agreement were calculated. The results showed that 75–81% of the precryoablation biopsies was correctly labelled ‘precryo’, and 48% of the postcryoablation biopsies as ‘postcryo’. The diagnostic yield of the three pathologists for precryo biopsies ranged between 67% and 71%, and between 48% and 71% for postcryo biopsies (not statistically different). When combining both types of biopsies, the overall diagnostic yield was 81% for all pathologists. The interobserver agreement was almost perfect for precryo biopsies, and substantial for postcryo biopsies. No complication occurred during or after any procedure; specifically no significant bleeding occurred after any biopsy. No needle-track seedings were noted, although follow up was relatively short for such evaluation. In conclusion, this study shows that it is feasible to obtain histopathological diagnoses from postcryoablation biopsies with a diagnostic yield and interobserver agreement similar to precryoablation biopsies. 3. Clinical outcome Cryoablation technology has evolved over the years. For example, in first and second generation cryosystems liquid nitrogen was used as a freezing agent, while in thirdgeneration cryoprobes pressurized argon gas is used for freezing. This transition permitted a decrease in cryoprobe diameter to 1.47mm (17Gauge). These smaller cryoprobes are easier to introduce into the kidney, minimize bleeding from the puncture tract, and reduce the risk of renal fracture. However, the ablation zone of a single cryoprobe is smaller therefore needing to insert multiple cryoprobes. Safety has been clinically proven, but concerns on efficacy of those small cryoprobes may exist. Several series have been published on the results of patients treated with large calibre cryoprobes, but mid and long term results are still scarce and most reports are retrospective. In chapter 6 we present mid term, functional and oncological results of patients exclusively treated with third generation 17G cryoprobes. We analyzed the data of 92 patients with 100 tumours treated in 95 sessions using 17G cryoprobes; type IceSeed (80%) or IceRod (20%). The mean follow up period of the cohort was 30.2 ± 16.5 months. General patient and procedural data, pathology outcome, renal function (based on serum creatinine and estimated glomerular filtration rates (eGFR)), imaging records (using CT or MRI), overall survival (OS), disease/recurrence free survival (D/RFS) and cancer specific survival (CSS) were assessed. Median age of the treated patients was 69 years (38.8-91.3). Mean tumour size was 2.5± 0.8 cm, and intraoperative biopsies showed 53.7% was RCC, 24.2% was benign, and 22.1% was nondiagnostic. The median number of cryoprobes used was 5 (3-8) in case of IceSeeds, and 3 (2-4) in case of IceRods. Renal function (eGFR) one year after ablation showed a preservation of renal function in 84.5% of those patients with a normal pre-ablation eGFR. In a multivariate analysis the only risk factor for eGFR-worsening was the previous eGFR. Tumour persistence at three months occurred in three cases (all RCC). Four radiological recurrences (all RCC) were detected during follow up at a median time of 23 (6-37) months. All these patients received additional treatment (RFA, radical or partial nephrectomy) after which they showed no suspicious radiological enhancement. The estimated mean RFS time and 3-year OS and RFS of patients with RCC was 47.8 months, 86.1% and 91.8%, respectively. These numbers were slightly higher in the group of patients including both RCC and unknown (nondiagnostic) tumour pathology. The CSS and DFS was 100% since none of the deaths were related to RCC and no patient developed metastatic disease during follow up. This study shows that laparoscopic cryoablation of small renal masses using 17G cryoprobes has a low primary failure rate and good functional outcome at mid term follow up. Chapter 7 shows the combined results using 17G cryoprobes for laparoscopic renal cryoablation of five European centres. Here the emphasis lies on patient characteristics and complication rate to identify risk factors for a negative outcome. Demographic data, comorbidity data, and American Society of Anaesthesiologists (ASA) scores were prospectively collected. Weighted and age-related comorbidities were retrospectively assigned according to the Charlson Comorbidity Index (CCI) and Charlson- Age Comorbidity Index (CACI). A negative outcome was defined as any undesired event, conversion to an open procedure, complication or deviation from the normal operative or postoperative course, sequel or failure to cure. Perioperative negative outcomes until 30 days after cryoablation were graded according to the Clavien criteria. A uni- and multivariate analysis were performed to identify independent risk factors for a negative outcome. A total of 144 patients were treated during 148 surgical sessions for 152 tumours. Median tumour size was 2.6 (1.0-5.6) cm, of which biopsies showed 65.8% was RCC, 15.1% benign pathology, and 15% was non-diagnostic (in 4% no biopsy was performed). Median ASA, CCI and CACI of patients were 2 (1-3), 2 (0-7), and 4 (0-11) respectively. Renal insufficiency, cardiac conditions, hypertension and COPD occurred in 33.2%, 30.4%, 18.9% and 12.8% of patients respectively, and 17.6% used anticoagulation regularly. Overall, 30 negative outcomes occurred in 25 cases (16.9%). Clavien grade 1, 2, and = 3 complications accounted for 50%, 28.5%, and 21.5% of all perioperative complications, respectively. Nine complications (30%) were directly attributable to the cryoablation. In the univariate analysis, ASA score, gender, the presence of a cardiac condition, tumour size, and the type of cryoneedle were significant predictors of negative outcome. In the subsequent multivariate logistic regression only gender, tumour size and the presence of a cardiac condition retained significance as independent predictors of negative outcome. A 3.4-cm tumour cut-off was found to predict a higher risk of perioperative negative outcomes. These results underscore the importance of a careful evaluation of patients’ cardiac condition and of tumour size when clinical advice is given on laparoscopic renal cryoablation. 165 Several interventional options exist for the treatment of small renal masses, namely laparoscopic or open partial nephrectomy, radiofrequency ablation and cryoablation. Active surveillance is emerging as a viable option in those patients with increased surgical risk. To be able to compare different therapies not only oncological and functional outcomes are important, but also the effect the therapy has on patients’ quality of life (QoL). Since no such data existed for patients treated by cryoablation, in chapter 8 we prospectively evaluated changes in QoL and postoperative pain in our series of patients. QoL was assessed using the Medical Outcome Study 36-item Short Form Health Survey (SF-36) and the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ-C30). Pain severity was evaluated using a Visual Analogue Scale (VAS). Baseline questionnaires and VAS were completed before cryosurgery. The SF-36 was completed 3 and 9 months after cryosurgery; the EORTC-QLQ-C30 2 weeks, 3 months, and 1 year after cryosurgery. Pain severity was assessed at day 1, 2 weeks, and 3 months postoperatively. The influence of the following parameters was statistically analyzed: 1) time of assessment, 2) patient age, 3) ASA score, 4) the occurrence of a complication, and 5) tumour histology based on intraoperative biopsy. The questionnaires and VAS of 57 patients with a total of 59 tumours were included in this study. Their age was as follows: younger than 60 years n=16; 60 to 70 years n=19; older than 70y n=22. Eight patients were ASA 1, 31 ASA 2, and 18 ASA 3. Biopsies showed 59.3% of tumours was RCC, 17% was benign, and 20.3% was non-diagnostic (in 3.4% no biopsy was taken). Overall, 12 complications occurred in 10 patients. The SF-36 analysis showed that compared with the general Dutch population only the general health perception of our patients were significantly lower, with age (older than 70 years) and tumour histology (RCC) as independent predictors. Concerning the EORTC-QLQ-C30, both time (2 weeks after surgery) and age older than 70 years were independent predictors of decreased physical functioning and pain. Time (2 weeks) and ASA 3 were independent predictors for nausea and vomiting, and age >70years and ASA 3 were independent predictors for constipation. The highest VAS score was reached 1 day after surgery and declined thereafter, however it had not returned to baseline levels after 3 months. Both time (1 day) and age >70y were independent predictors for a high VAS score. This study shows that QoL of patients treated with laparoscopic renal cryoablation shows a relative decrease two weeks after surgery, which has normalized after three months. Age and comorbidities (reflected in the ASA score) especially affect QoL negatively. VAS showed a peak one day after surgery, especially in patients older than 70 years. 4. Radiological follow up As stated earlier, in cryosurgery the renal tumour is ablated in situ. This means that there is no surgical specimen to obtain a histopathological diagnosis and to check ‘ablative margins’. Treatment success therefore is determined by the use of imaging techniques such as CT and MRI. Chapter 9 describes the characteristics and development of so called ‘cryolesions’ on contrast-enhanced CT images and its relationship with the intraoperative biopsy outcome. The contrast-enhanced CT images of 26 patients with a follow up of =6 months were analyzed by one radiologist. A CT was performed preoperatively, and 3, 6, 9, 12, 18, 24, 30 and 36 months after cryoablation. The diameter of the cryolesion was measured, enhancement patterns were described, and other abnormal findings were noted. The mean follow up of the patients was 17.2 (6-36) months. Mean tumour size was 2.4 (1.3-3.8) cm, with biopsies showing 11 RCCs, 4 oncocytomas, 1 AML, and 7 non-diagnostic (of 3 tumours no biopsy was taken). One cryolesion showed residual tumour on the first scan after treatment. Of the other 25 cryolesions 20% showed rim-enhancement after treatment, including one also showing focal enhancement. This enhancement disappeared within 6 months. All cryolesions showed nonenhancing infiltration of the perirenal fatty tissue. The mean diameter of the cryolesions decreased by 38% in 12 months. These results were independent of histopathological diagnosis. Although the size of the series is relatively small and there is no pathological confirmation of our findings, this study suggests that the presence of rim enhancement in the first months after cryoablation is relatively common and does not justify immediate retreatment.
Originele taal-2Engels
KwalificatieDoctor in de Filosofie
Toekennende instantie
  • Academic Medical Centre Amsterdam
  • de la Rosette, Jean J.M.C.H., Promotor, Externe Persoon
  • Wijkstra, Hessel, Co-Promotor
  • Laguna Pes, M.P., Co-Promotor, Externe Persoon
Datum van toekenning11 jan 2012
Plaats van publicatieAmsterdam
Gedrukte ISBN's978-94-90861-03-2
StatusGepubliceerd - 2012

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