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Non-Surgical Ablative Treatments for Small Renal Tumours Less Than 4 cm
european urology supplements 5 (2006) 533–536
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Non-Surgical Ablative Treatments for Small Renal Tumours Less Than 4 cm Peter Whelan Department of Urology, St James University Hospital, Leeds, UK
Article info
Abstract
Keywords: Ablative treatment Cryoablation HIFU Radiofrequency ablation Renal cell carcinoma
Introduction and objectives: Non-Surgical Ablative Treatments of renal tumors represent an attractive alternative approach for small lesions (<4 cm) in selected patients. Aim of this study is to extensively assess the evidences and indications of this conservative approach and to provide notion of technical aspects. Methods: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1999 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: Cryoablation, radiofrequency and HIFU ablation represent the current available non-surgical ablative treatments for renal cell carcinoma (RCC). Indications for this conservative approach are widening and include RCC in a solitary or transplant kidney, synchronous bilateral primary tumors, RCC local recurrence in absence of metastatic disease, and RCC in patients with von Hippel-Lyndau. Cryoblation has been more extensively studied. It is based on cells freezing and consequently disruption of cell membranes and proteins. Multiple lesions can be treated and the procedures can be repeated. Radiofrequency ablation, as well as cryoablation, can be delivered via an open, laparoscopic or percutaneous approach. It delivers a monopole alternative current and it is associated with optimal 5-year follow-up in patients with RCC volume less than 3 cm. Morbidity rate of these approaches was up to 14%. Limited data are available for HIFU ablation. Conclusions: Non surgical ablative approach seems to represent an attractive alternative treatment for small RCC (<4 cm) in selected patients, due to the immense improvement in imaging techniques, the ability to be delivered to specific targeted lesions and the opportunity to be repeated. However, future well-designed studies are needed to formally assess and confirm the long term oncological results of these approaches. # 2006 Published by Elsevier B.V.
E-mail address: [email protected]. 1569-9056/$ – see front matter # 2006 Published by Elsevier B.V. doi:10.1016/j.eursup.2006.02.022
534
european urology supplements 5 (2006) 533–536
The routine use of ultrasonography in upper abdominal operations has, over the last decade or more, yielded an increasingly high diagnosis of small renal lesions. Whilst initially these lesions (small meaning <4 cm in diameter in this context) were treated conventionally by radical nephrectomy, it was found that up to 15% of these lesions, especially those less than 2 cm, were benign and that radical nephrectomy was seen to be an overtreatment with a significant loss of functioning renal tissue. This finding has led over the last decade to an increase in the utilisation of partial nephrectomy, whether delivered by an open procedure or by laparoscopy, to deal not only with true renal cell carcinomas but also to remove benign lesions (some of which may have potential malignancy), but with the aim of preserving a significant portion of renal function on the affected side. In addition, many lesions that have the characteristic imaging appearances of a renal cell carcinoma are found in patients who are unfit for extirpated surgery—be it radical nephrectomy or partial nephrectomy—and therefore, up to now, have been denied any reliable method of destroying the lesion, as the conventional treatment has hitherto been that of observation, possibly supplemented by selective tumour embolisation in response to significant haematuria. A potential indication for patients is widening; potential additional indications for any non-surgical ablative procedure now include the following: A renal cell carcinoma in a solitary or transplant kidney in which even a partial nephrectomy could compromise renal function. Synchronous bilateral primary renal cell carcinomas in which the smaller carcinoma may be dealt with by a non-surgical technique. Local recurrence of renal cell carcinoma frequently within a lymph node, especially if there is no evidence of metastatic disease elsewhere but the patient has significant co-morbidity factors. Patients with von Hippel-Lindau syndrome who are prone to developing multiple renal cell carcinomas and whose alternative therapy may well be early bilateral nephrectomy with dialysis.
the most experimental and controversial group of all—patients who are otherwise fit for partial nephrectomy but who may be opting (unfortunately in light of relatively little longitudinal information) to use non-invasive therapy as the treatment of choice. Three therapies have been utilised in the last decade: cryoablation, radiofrequency ablation (RFA), and high intensity focused ultrasonography (HIFU) ablation.
1.
In light of the specific circumstances alluded to above, it is well recognised in other malignancies including urological ones such as prostate cancer (in which brachytherapy has found great favour with the patient population) that non-surgical procedures—if they are safe and efficient—are highly acceptable to patients. Formal assessment with well-constructed trials is essential before therapies are taken up, not because they are fashionable or easy but because they represent the possibility that effective and possibly repeatable therapy with minimal side effects could be denied to a patient. Therefore, strong evidence data are required. Because of the continuing lack of long-term data on the oncological control equivalence between partial nephrectomy and radical nephrectomy, it is essential to carry out studies that seek to be able to show that a partial nephrectomy can achieve the following goals: 1. Equivalent cancer control must be demonstrated. 2. There must be confirmation that the tumour has been eradicated. 3. Maximal renal unit preservation and function must be demonstrated. 4. There is a reduced overall morbidity in comparison with surgical procedures. 5. There must be demonstrable benefits to quality of life. 6. There must be demonstrable financial benefits to the health care system. 1.1.
More experimental procedures, which require formal phase I and II studies, are needed urgently in light of the new oral preparations against metastatic renal cell carcinoma. These studies should include patients with metastatic renal cell carcinoma who would benefit ideally from a debulking nephrectomy before medical therapy and—in
Rationale for the use of new therapies
Cryoblation
This method of local control has been used widely over the last decade and depends on the lethal effects of freezing, thereby producing disruption to cell membranes, proteins and organelles as well as vascular damage. The end result of the process is coagulated necrosis with a 2- to 5-mm rim of
european urology supplements 5 (2006) 533–536
partial necrosis, and with the lesion being replaced by fibrosis at 1 year and then a measurable volume decrease between 25% and 40% occurring within 3 months of treatment. Much of the work initially has used animal models, mainly the sheep and the dog. The principle ends in a constant-sized ice ball by using argon to freeze and helium to thaw with a double freeze/ thaw method achieving temperatures of 140 8C to 80 8C at the ice ball’s tip and 40 8C at its edge. A temperature of 9.4 8C is necessary to kill renal tissue and 40 8C to kill cancer cells. The ice balls can be monitored by ultrasonography in open and laparoscopic cases, and by computed tomography (CT) or magnetic resonance imaging (MRI) in percutaneous cases. 1.2.
Cryoblation technique
There should be minimal disturbance in accessing the lesion. It is recommended that a biopsy of the lesion be taken before commencement of the procedure and that thermositors and probes be inserted under imaging control. The double-freeze method with an active thaw after the first freeze (using helium) and a passive thaw after the second freeze (allowing the temperature to normalize) is undertaken, and, on the raw surface, either a Spongistan (Johnson & Johnson, Skipton, UK) or Surgicel (Ethicon, Johnson & Johnson, Somerville, NJ, USA) can be placed over the area either during the open or laparoscopic procedure. No such haemostasis is utilised in the percutaneous technique. There are a variety of methods of follow-up for this technique, but hitherto CT scanning at 6-month intervals for 2 years and then an annual ultrasonography has been utilised. In a small series from Cambridge [1], in 10 with patients with von HippelLandau disease, 14 solid lesions of a mean size of 2.6 cm (range, 2 to 3.1 cm) were treated; the tumours were of good pathology with a Fuhrman score of 1 or 2. In two patients, there was a fall of haemoglobin greater than 3 grams, but neither required transfusion. The mean length of stay was 4 days, with a median follow-up of 12 months. At a range of 6–24 months, 13 of the 14 lesions had shown no enhancement and had fallen to a size of 1.1 cm. A recent study by Weld & Landman [2] looked at eight published series using cryoablation in a total of 326 patients, who had been followed for a range of 8 to 49.3 months. Of the 326 patients, 195 underwent laparoscopy, 41 underwent open surgery, and 90 received MRI-guided percutaneous treatment. Overall there was persistent or recurrent disease in 15 (4.6%) and morbidity of 10.6% (representing
535
23 of 226 patients with no information being available for the remaining 100 patients). 1.3.
Radiofrequency ablation
RFA probes deliver a monopole alternative current of 400 to 500 kilohertz. This similarly achieved an expanding sphere of chronic necrosis and, as with cryoablation, RFA can be delivered via an open or a laparoscopic surgical approach or by a percutaneous method. In a summary of reported cases by Weld & Landman [2], a combined total of 277 cases were seen with a mean follow-up of only 10 months. Persistent or recurrent disease rate was 7.9%; the complication rate was 13.9%. Most work on RFA has been carried out by the Massachusetts General Hospital group in Boston, MA, USA (Professor P. R. Mueller) Their initial paper [3] in 1999 showed an encouraging first principle. Their recent publication [4] in 2005 has shown long-term follow-up of patients with renal cell carcinoma treated by radiofrequency ablation in tumours less than 3 cm. This series has shown no recurrent disease at a 5-year follow-up. In our own institution’s small series [5], treatments of 35 renal cell carcinomas in 25 patients over 15 months have shown highly encouraging preliminary results similar to those of the Massachusetts General Hospital Group. (In keeping with the importance of knowing how well these cases are doing and whether true cancer control is being achieved, an intense initial assessment and radiological follow up programme is in progress.) 1.4.
RFA technique
At this time, RFA is carried out percutaneously by using guided ultrasonography, with or without contrast depending on accessibility. The staging of the tumour is carried out initially with contrastenhanced CT of the kidney, and the monitoring for treatment efficacy is done by contrast-enhanced MRI. The following assessments using contrastenhanced MRIU are carried out at 1, 3, 6 and 12 months post-RFA and annually over the first year. Ultrasonography with or without contrast enhancement would be utilised if further treatment was deemed necessary, and CT enhanced imaging would be used if restaging of the patient was necessary. 1.5.
HIFU ablation
Currently, very limited data on HIFU ablation are available, so this modality has not been reviewed.
536
2.
european urology supplements 5 (2006) 533–536
Conclusions
The ability to destroy malignant lesions in situ when they are still at a small stage and the possibility of tumour eradication coupled with maximum preservation of renal tissue is an ideal goal. Because of the immense improvement in imaging techniques, the ability to deliver both cryoablation and RFA to specific targeted lesions, the opportunity to repeat these treatments and the chance that the oncological cure rate, as indicated by the radiofrequency studies from the Massachusetts General Hospital group, may mean that an effective treatment that does not require surgery may be within our hands. However, more importantly, it is essential that specific long-term oncological data with any long-term side effects be accumulated because, faced with a choice of treatments, many patients will go with what is perceived as the easier treatment (ie, the non-surgical treatment). Therefore, there must be evidence-based data that, if they do so, they are not placing cure of their renal cell cancer at risk. However, as smaller lesions are found in which the possibility that many of these will be benign, non-surgical therapies would seem to be increasingly indicated. It is therefore essential that we move our own paradigm of the management of renal cell cancer to
embrace the fact that many lesions are going to be small and, therefore, probably all lesions, as they do in most other malignancies, will require prior biopsy rather than, as we have hitherto done because of the size and the obvious nature of the lesion, proceeding to ablative therapy without a pre-treatment histological confirmation of the diagnosis.
References [1] Doble A, Riddick A, Hegarty P, Taylor H. Renal cryoablation in Von Hipple Lindau disease. Presented at BUAS Meeting. Glasgow 2005. [2] Weld JK, Landman J. Comparison of cryoablation, radio frequency ablation, land HIFU for treating small renal tumours. BJUI 2005;96:1224–9. [3] McGovern FJ, Wood BJ, Goldberg SN, Mueller PR. Radiofrequency ablation of renal cell carcinoma via image guided needle electrodes. J Urol 1999;161:599–600. [4] McDougal WS, Gervais DA, McGovern FS, Mueller PR. Long term follow up of patients with renal cell carcinoma treated with radio frequency ablation with curative intent. J Urol 2005;174:61–3. [5] Wah TM, Irving HC, Wilson D. Radio frequency ablation of renal cell carcinoma; imaging assessment pre- one month post-RFA with contrast enhanced US, CT, and MRI—a pilot study. Accepted as a work in progress for the World Congress of Intervention Oncology. Italy 2006.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Non-Surgical Ablative Treatments for Small Renal Tumours Less Than 4 cm Peter Whelan Department of Urology, St James University Hospital, Leeds, UK
Article info
Abstract
Keywords: Ablative treatment Cryoablation HIFU Radiofrequency ablation Renal cell carcinoma
Introduction and objectives: Non-Surgical Ablative Treatments of renal tumors represent an attractive alternative approach for small lesions (<4 cm) in selected patients. Aim of this study is to extensively assess the evidences and indications of this conservative approach and to provide notion of technical aspects. Methods: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1999 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: Cryoablation, radiofrequency and HIFU ablation represent the current available non-surgical ablative treatments for renal cell carcinoma (RCC). Indications for this conservative approach are widening and include RCC in a solitary or transplant kidney, synchronous bilateral primary tumors, RCC local recurrence in absence of metastatic disease, and RCC in patients with von Hippel-Lyndau. Cryoblation has been more extensively studied. It is based on cells freezing and consequently disruption of cell membranes and proteins. Multiple lesions can be treated and the procedures can be repeated. Radiofrequency ablation, as well as cryoablation, can be delivered via an open, laparoscopic or percutaneous approach. It delivers a monopole alternative current and it is associated with optimal 5-year follow-up in patients with RCC volume less than 3 cm. Morbidity rate of these approaches was up to 14%. Limited data are available for HIFU ablation. Conclusions: Non surgical ablative approach seems to represent an attractive alternative treatment for small RCC (<4 cm) in selected patients, due to the immense improvement in imaging techniques, the ability to be delivered to specific targeted lesions and the opportunity to be repeated. However, future well-designed studies are needed to formally assess and confirm the long term oncological results of these approaches. # 2006 Published by Elsevier B.V.
E-mail address: [email protected]. 1569-9056/$ – see front matter # 2006 Published by Elsevier B.V. doi:10.1016/j.eursup.2006.02.022
534
european urology supplements 5 (2006) 533–536
The routine use of ultrasonography in upper abdominal operations has, over the last decade or more, yielded an increasingly high diagnosis of small renal lesions. Whilst initially these lesions (small meaning <4 cm in diameter in this context) were treated conventionally by radical nephrectomy, it was found that up to 15% of these lesions, especially those less than 2 cm, were benign and that radical nephrectomy was seen to be an overtreatment with a significant loss of functioning renal tissue. This finding has led over the last decade to an increase in the utilisation of partial nephrectomy, whether delivered by an open procedure or by laparoscopy, to deal not only with true renal cell carcinomas but also to remove benign lesions (some of which may have potential malignancy), but with the aim of preserving a significant portion of renal function on the affected side. In addition, many lesions that have the characteristic imaging appearances of a renal cell carcinoma are found in patients who are unfit for extirpated surgery—be it radical nephrectomy or partial nephrectomy—and therefore, up to now, have been denied any reliable method of destroying the lesion, as the conventional treatment has hitherto been that of observation, possibly supplemented by selective tumour embolisation in response to significant haematuria. A potential indication for patients is widening; potential additional indications for any non-surgical ablative procedure now include the following: A renal cell carcinoma in a solitary or transplant kidney in which even a partial nephrectomy could compromise renal function. Synchronous bilateral primary renal cell carcinomas in which the smaller carcinoma may be dealt with by a non-surgical technique. Local recurrence of renal cell carcinoma frequently within a lymph node, especially if there is no evidence of metastatic disease elsewhere but the patient has significant co-morbidity factors. Patients with von Hippel-Lindau syndrome who are prone to developing multiple renal cell carcinomas and whose alternative therapy may well be early bilateral nephrectomy with dialysis.
the most experimental and controversial group of all—patients who are otherwise fit for partial nephrectomy but who may be opting (unfortunately in light of relatively little longitudinal information) to use non-invasive therapy as the treatment of choice. Three therapies have been utilised in the last decade: cryoablation, radiofrequency ablation (RFA), and high intensity focused ultrasonography (HIFU) ablation.
1.
In light of the specific circumstances alluded to above, it is well recognised in other malignancies including urological ones such as prostate cancer (in which brachytherapy has found great favour with the patient population) that non-surgical procedures—if they are safe and efficient—are highly acceptable to patients. Formal assessment with well-constructed trials is essential before therapies are taken up, not because they are fashionable or easy but because they represent the possibility that effective and possibly repeatable therapy with minimal side effects could be denied to a patient. Therefore, strong evidence data are required. Because of the continuing lack of long-term data on the oncological control equivalence between partial nephrectomy and radical nephrectomy, it is essential to carry out studies that seek to be able to show that a partial nephrectomy can achieve the following goals: 1. Equivalent cancer control must be demonstrated. 2. There must be confirmation that the tumour has been eradicated. 3. Maximal renal unit preservation and function must be demonstrated. 4. There is a reduced overall morbidity in comparison with surgical procedures. 5. There must be demonstrable benefits to quality of life. 6. There must be demonstrable financial benefits to the health care system. 1.1.
More experimental procedures, which require formal phase I and II studies, are needed urgently in light of the new oral preparations against metastatic renal cell carcinoma. These studies should include patients with metastatic renal cell carcinoma who would benefit ideally from a debulking nephrectomy before medical therapy and—in
Rationale for the use of new therapies
Cryoblation
This method of local control has been used widely over the last decade and depends on the lethal effects of freezing, thereby producing disruption to cell membranes, proteins and organelles as well as vascular damage. The end result of the process is coagulated necrosis with a 2- to 5-mm rim of
european urology supplements 5 (2006) 533–536
partial necrosis, and with the lesion being replaced by fibrosis at 1 year and then a measurable volume decrease between 25% and 40% occurring within 3 months of treatment. Much of the work initially has used animal models, mainly the sheep and the dog. The principle ends in a constant-sized ice ball by using argon to freeze and helium to thaw with a double freeze/ thaw method achieving temperatures of 140 8C to 80 8C at the ice ball’s tip and 40 8C at its edge. A temperature of 9.4 8C is necessary to kill renal tissue and 40 8C to kill cancer cells. The ice balls can be monitored by ultrasonography in open and laparoscopic cases, and by computed tomography (CT) or magnetic resonance imaging (MRI) in percutaneous cases. 1.2.
Cryoblation technique
There should be minimal disturbance in accessing the lesion. It is recommended that a biopsy of the lesion be taken before commencement of the procedure and that thermositors and probes be inserted under imaging control. The double-freeze method with an active thaw after the first freeze (using helium) and a passive thaw after the second freeze (allowing the temperature to normalize) is undertaken, and, on the raw surface, either a Spongistan (Johnson & Johnson, Skipton, UK) or Surgicel (Ethicon, Johnson & Johnson, Somerville, NJ, USA) can be placed over the area either during the open or laparoscopic procedure. No such haemostasis is utilised in the percutaneous technique. There are a variety of methods of follow-up for this technique, but hitherto CT scanning at 6-month intervals for 2 years and then an annual ultrasonography has been utilised. In a small series from Cambridge [1], in 10 with patients with von HippelLandau disease, 14 solid lesions of a mean size of 2.6 cm (range, 2 to 3.1 cm) were treated; the tumours were of good pathology with a Fuhrman score of 1 or 2. In two patients, there was a fall of haemoglobin greater than 3 grams, but neither required transfusion. The mean length of stay was 4 days, with a median follow-up of 12 months. At a range of 6–24 months, 13 of the 14 lesions had shown no enhancement and had fallen to a size of 1.1 cm. A recent study by Weld & Landman [2] looked at eight published series using cryoablation in a total of 326 patients, who had been followed for a range of 8 to 49.3 months. Of the 326 patients, 195 underwent laparoscopy, 41 underwent open surgery, and 90 received MRI-guided percutaneous treatment. Overall there was persistent or recurrent disease in 15 (4.6%) and morbidity of 10.6% (representing
535
23 of 226 patients with no information being available for the remaining 100 patients). 1.3.
Radiofrequency ablation
RFA probes deliver a monopole alternative current of 400 to 500 kilohertz. This similarly achieved an expanding sphere of chronic necrosis and, as with cryoablation, RFA can be delivered via an open or a laparoscopic surgical approach or by a percutaneous method. In a summary of reported cases by Weld & Landman [2], a combined total of 277 cases were seen with a mean follow-up of only 10 months. Persistent or recurrent disease rate was 7.9%; the complication rate was 13.9%. Most work on RFA has been carried out by the Massachusetts General Hospital group in Boston, MA, USA (Professor P. R. Mueller) Their initial paper [3] in 1999 showed an encouraging first principle. Their recent publication [4] in 2005 has shown long-term follow-up of patients with renal cell carcinoma treated by radiofrequency ablation in tumours less than 3 cm. This series has shown no recurrent disease at a 5-year follow-up. In our own institution’s small series [5], treatments of 35 renal cell carcinomas in 25 patients over 15 months have shown highly encouraging preliminary results similar to those of the Massachusetts General Hospital Group. (In keeping with the importance of knowing how well these cases are doing and whether true cancer control is being achieved, an intense initial assessment and radiological follow up programme is in progress.) 1.4.
RFA technique
At this time, RFA is carried out percutaneously by using guided ultrasonography, with or without contrast depending on accessibility. The staging of the tumour is carried out initially with contrastenhanced CT of the kidney, and the monitoring for treatment efficacy is done by contrast-enhanced MRI. The following assessments using contrastenhanced MRIU are carried out at 1, 3, 6 and 12 months post-RFA and annually over the first year. Ultrasonography with or without contrast enhancement would be utilised if further treatment was deemed necessary, and CT enhanced imaging would be used if restaging of the patient was necessary. 1.5.
HIFU ablation
Currently, very limited data on HIFU ablation are available, so this modality has not been reviewed.
536
2.
european urology supplements 5 (2006) 533–536
Conclusions
The ability to destroy malignant lesions in situ when they are still at a small stage and the possibility of tumour eradication coupled with maximum preservation of renal tissue is an ideal goal. Because of the immense improvement in imaging techniques, the ability to deliver both cryoablation and RFA to specific targeted lesions, the opportunity to repeat these treatments and the chance that the oncological cure rate, as indicated by the radiofrequency studies from the Massachusetts General Hospital group, may mean that an effective treatment that does not require surgery may be within our hands. However, more importantly, it is essential that specific long-term oncological data with any long-term side effects be accumulated because, faced with a choice of treatments, many patients will go with what is perceived as the easier treatment (ie, the non-surgical treatment). Therefore, there must be evidence-based data that, if they do so, they are not placing cure of their renal cell cancer at risk. However, as smaller lesions are found in which the possibility that many of these will be benign, non-surgical therapies would seem to be increasingly indicated. It is therefore essential that we move our own paradigm of the management of renal cell cancer to
embrace the fact that many lesions are going to be small and, therefore, probably all lesions, as they do in most other malignancies, will require prior biopsy rather than, as we have hitherto done because of the size and the obvious nature of the lesion, proceeding to ablative therapy without a pre-treatment histological confirmation of the diagnosis.
References [1] Doble A, Riddick A, Hegarty P, Taylor H. Renal cryoablation in Von Hipple Lindau disease. Presented at BUAS Meeting. Glasgow 2005. [2] Weld JK, Landman J. Comparison of cryoablation, radio frequency ablation, land HIFU for treating small renal tumours. BJUI 2005;96:1224–9. [3] McGovern FJ, Wood BJ, Goldberg SN, Mueller PR. Radiofrequency ablation of renal cell carcinoma via image guided needle electrodes. J Urol 1999;161:599–600. [4] McDougal WS, Gervais DA, McGovern FS, Mueller PR. Long term follow up of patients with renal cell carcinoma treated with radio frequency ablation with curative intent. J Urol 2005;174:61–3. [5] Wah TM, Irving HC, Wilson D. Radio frequency ablation of renal cell carcinoma; imaging assessment pre- one month post-RFA with contrast enhanced US, CT, and MRI—a pilot study. Accepted as a work in progress for the World Congress of Intervention Oncology. Italy 2006.