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Eur J Cardiothorac Surg 2006;30:177-183
© 2006 Elsevier Science NL
a Cardiac and Thoracic Department, Via Paradisa 2, 56124 Pisa, Italy
b Department of Surgery, Via Paradisa 2, 56124 Pisa, Italy
Received 21 February 2006; received in revised form 23 March 2006; accepted 30 March 2006.
* Corresponding author. Tel.: +39 050 995211; fax: +39 050 577239. (Email: m.ambrogi{at}med.unipi.it).
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Key Words: Lung cancer • Pulmonary metastasis • Radiofrequency ablation • Percutaneous thermal ablation • Minimally invasive treatment
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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The lung is then the second most frequent site of metastatic disease, and several studies reported that, in selected cases, surgical resection of pulmonary metastasis represents a viable option of treatment [3].
Nevertheless, surgical treatment is not always feasible. Patients with NSCLC, in fact, are frequently poor surgical candidates because of coexistent chronic obstructive broncho-pneumopathy or other associated diseases. It is estimated that more than 20% of patients with stage I or II NSCLC would not undergo surgical resection [4]. On the other hand, in patients with pulmonary metastasis, the number and location of the lesions could require a sacrifice of pulmonary parenchyma, which is out of proportion with the aim of this therapeutic option, often palliative. And, again, it should be considered that the costs/benefits ratio of the surgical treatment, in patents with a stage IV neoplasm, is not always in proportion with the results in terms of survival and quality of life.
In this scenario, it is comprehensible that minimally invasive treatments often receive great interest, as is happening for radiofrequency ablation (RFA). This method has been successfully used for the treatment of hepatocellular carcinoma [5], hepatic metastases [6], osteoid osteoma [7] and other solid tumours [8–10]. Thin metallic probes, similar to aspiration biopsy needles, are percutaneously inserted into the lesion using computed tomography (CT) scanning or ultrasound guidance. Radiofrequency energy is then applied in order to achieve a temperature greater than 60 °C (in most cases 90 °C). Thus, coagulative necrosis of the tumour is induced in a controlled manner.
More recently, this technique has been applied to pulmonary tumours, too, with promising preliminary results [11–20]. All recent clinical trials reported, in fact, a good local response, with an elevated tolerability and a very low rate of complications. However, these trials have a short follow-up period and little is yet understood about the efficacy of RFA in the mid-to-long term.
The object of this paper concerns the experience of a single referral centre regarding radiofrequency ablation of lung tumours, with particular reference to the results in the intermediate period.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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The primary endpoint was local disease-free survival, while secondary endpoints included overall survival and side effects.
2.1 Radiofrequency generator and devices
We utilised a generator able to provide monopolar radiofrequency energy to perform coagulation and ablation of soft tissue (Model 1500, RITA Medical System, Mountain View, CA, USA). This is an automatic apparatus with a max power output of 150 W, operating at 460 Hz. It has multiple temperature displays as well as impedance and power monitoring. The energy was transferred into the tissue by means of a multitined expandable array (StarBrust XL, RITA Medical system). It consists of a 15-gauge needle cannula with nine deployable electrodes which open flower-like up to 5 cm (Fig. 1
). Five electrodes are equipped with thermocouples which allow continuous measurement of the temperature inside the tissue. Two grounding pads were applied to each shaved leg to ground the current and to reduce risks of skin heat injuries. Once the system was powered up, the physician set the parameters of the ablation: the mode of operation (we utilised ‘average temperature mode’, in which delivered power was automatically regulated to maintain the target temperature set); the target temperature; the ablation time at target temperature; the maximum power delivery level, which can be modified at any time during the procedure.
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Main contra-indications to surgery were as follows: comorbidity, poor lung function (even for a limited resection), previous repeated operations on the same lung, distribution and site of the lesions (which would have required an intolerable sacrifice of lung parenchyma).
Preoperative proof of lung malignancy was achieved systematically by biopsy of the lesion in all the first 30 patients of our series and then when there was a clinical doubt. Either new or increasing lung lesions at plain chest radiographs or CT scans, particularly in patients at risk for NSCLC or with a history of cancer, were considered clinical proof of malignancy (in some cases supported by PET scans too).
Patients with metastatic disease were treated if the primary cancer was cured or controlled, and after exclusion of other sites of disease (by PET scan in most cases).
All patients were required to sign a written informed consent, after adequate explanation of risks and benefits of the procedure.
2.3 RFA procedure and follow-up
All the procedures were performed with the patients under conscious sedation (usually achieved with administration of ketorolac 0.5–0.8 mg/kg, propofol 1–2 mg/(kg h) and remifentanil 0.1 mg/(kg/min)) and local anaesthesia (subcutaneous 1% xylocaine). Vital signs of the patient were non-invasively monitored continuously. We always utilised CT guidance, enhanced by contrast media before and after the procedure, in order to obtain more information about effectiveness. In all cases the target temperature was 90 °C. It was maintained for a time which ranged from 15 to 27 min according to the size of the tumour, which also determined the deployment of the electrodes. These last were deployed gradually, starting from 2 cm and then 1 cm for each step. When technically possible, we always pursued the objective of encompassing the tumour with an ablation zone at least 1 cm larger (Fig. 2
). After the procedure, all patients were transferred to the recovery room for observation. Twenty-four hours later, after a chest radiograph to exclude complications (such as a pneumothorax), the patients were discharged. Radiological follow-up included contrast-enhanced CT at 1, 3 and 6 months and then at 6 months intervals. CT scans were evaluated by two physicians, the same thoracic surgeon who performed the procedure and a radiologist. First evaluation was done just after RFA with a post-procedural CT enhanced with contrast material. A procedure was considered technically successful when it was performed according to the protocol, and the ablation zone completely covered the tumour with lower enhancement than before RFA. Effectiveness was calculated starting from the 1st month follow-up in terms of a local control of the disease. Due to a frequent increase of the lesion immediately after RFA, resulting from the sum of the tumour and the ablation zone, at the 1st and 3rd month follow-up the main criteria for complete response was reduction of the contrast material enhancement, in respect to that measured before the procedural. However, a value of the lesion's density greater than 25 Hounsfield Unit (HU) was considered indicative of persistence or relapse of the disease. The dimensional criteria, instead, became the main criteria from the 6th month on, in accordance with the RECIST criteria [21]. An increase of the size of the lesion in respect to its size pre-RFA was considered a persistence or relapse of the disease, and therefore a failure of the procedure. However, both criteria, the size and the enhancement, have been considered and integrated at all times, case by case, to determine whether progression had occurred. In five cases a PET scan was utilised to better assess recurrence, or lack of recurrence, of the lesion.
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2.4 Statistical analysis
Descriptive statistics for the series were generated with STATISTICA software (StatSoft Inc., Tulsa, OK, USA; version 6.0 for Windows). Comparisons of percentages and mean values were performed by using Student's t-test. Kaplan–Meier with log-rank analysis was used to calculate overall survival and local progression-free interval and to compare patients. A value of p less than 0.05 was considered to indicate a statistically significant difference.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Time of RFA at target temperature was 19 min on average (range of 15–27). The mean time to reach the target temperature was 4 min (range of 2–8), which includes the time necessary to reach the target temperature again after deployment of the electrodes.
In all cases, except two, the procedure was technically successful. In one patient, probably due to the density of the tumour, we did not succeed in inserting the needle into the lesion, which was pushed against the oesophagus and inferior cava vein. In this case we renounced the RFA, and this patient was excluded from further evaluation in the study. In another patient the procedure was interrupted 5 min before the programmed time due to a high impedance level.
All the procedures were tolerated well. Five patients, with lesion near or in contact with the pleural surface, experienced pain related to RFA which required the deepening of sedation and that, however, cleared up in a few minutes after the end of the procedure.
We had no mortality, whilst morbidity affected 12 patients (15.2% of the procedures). Complications consisted of 10 cases of partial pneumothorax (12.7%), 6 of which required pleural drainage, 1 pleural effusion, which was resolved with medical treatment, and 1 chest wall haematoma.
Mean post-procedural hospital stay was 1.3 days (range of 1–4).
3.1 Response rates and survival analysis
At a mean follow-up period of 23.7 months (median 24, range of 6–50), the overall radiological complete response rate was 61.9% (39/63 lesions). It seemed to be better for lesions smaller than 3 cm (69.7% vs 50%) and for metastases from extra-thoracic malignancies (70.8% vs 56.4%), even if neither reached statistical significance.
Thirty-one of 54 (60%) patients were alive, and among these 24 (77%) were locally disease-free (LDF); of the patients who were deceased 15 (65%) were LDF. Distant recurrence (mediastinal, pulmonary or other sites) occurred in 21 (39%) patients (5 of them were LDF). Most of these patients underwent some adjuvant therapy (CT and/or RT). Mean overall survival and local progression-free interval (LPI) were 17.3 and 12.9 months, respectively. They were related to the size of the tumour, both showing a difference between lesions smaller than 3 cm and those equal or greater than 3 cm. Survival was 19.7 months for lesions smaller than 3 cm and 12.1 months for those greater (p = .02), while LPI was 15.8 and 6.6 months, respectively (p = .002).
The Kaplan–Meier curves represent the overall actuarial survival in Fig. 3 , whilst they compare survival between NSCLC and metastasis in Fig. 4 , and between lesions greater or smaller than 3 cm in Fig. 5 . Median overall survival is 28.9 months; it decreases to 18.9 for NSCLC, and is not reached for metastases (without statistical significance), whilst it increases to 30.5 months in cases of tumours smaller than 3 cm versus 14.9 months for lesions equal to or larger than 3 cm (still without statistical significance, p = .08). Median overall LPI is 24.1 months, without statistical significance between NSCLC and metastasis, whilst it is statistically significant when we compare tumours equal to or larger than 3 cm versus those smaller (p = .04) (Fig. 6 ).
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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The first percutaneous RFA of a lung tumour is reported by Dupuy et al. [11] in 2000. He treated three patients, in whom the main purpose of utilizing RFA was palliation, with results which were technically successful and uneventful. Since that paper, a number of manuscripts have described the feasibility and safety of the procedure. In particular, an international study survey, reported by Steinke et al. [15] in 2004, stressed, with almost 500 RFA of lung tumours collected, how percutaneous pulmonary RFA seems to be a minimally invasive tool for local control with negligible mortality, low morbidity, short hospital stay and gain in quality of life.
Unlike feasibility and safety, efficacy seems not to be so easily assessable. Contrary to surgical resection, where cancer is removed, in fact, treatment response to RFA is valuable only with radiological follow-up. After RFA, an ablation zone is generally visible at CT scan as a ground glass opacity encompassing the target tumour. In most cases, the ablation zone involves a larger area than the original tumour, especially just after RFA and for the 1st months. As a consequence, in this period, the dimensional criteria are not very useful. This is the reason that some authors utilise CT densitometry protocols to help evaluate for persistent or recurrent disease [13]. Other centres, instead, have been using a modification of the RECIST criteria to assess tumour progression at follow-up [11]. In our experience we utilised both criteria, privileging enhancement after contrast material injection during the first 3 months after RFA, and, afterwards, the dimensional criteria in accordance with the RECIST. However, both radiological features of the lesions, the size and the density, were contemporarily evaluated every time and in all patients, together with other features, in order to assess treatment response. Moreover, when necessary, a PET scan was performed to clear doubts, and to decide either when to proceed to further treatment (often we repeated RFA) or to wait. Perhaps, a more useful tool in the follow-up of these patients could be PET-CT, as recently reported by Griffo et al., in an abstract at the 3rd EACTS/ESTS Joint Meeting, held in Leipzig on 13th September 2004 [23].
Another issue, on which attention is currently focused, is the response to RFA treatment of lung tumours in the mid-to-long term. Most of the papers, in fact, report preliminary results in the short period. In Table 2 are reported the complete response rates and the follow-up period of the most significant studies reported in the literature. It seems that that the longer the follow-up is, the worse is the complete response rate. So it will be interesting to see in the mid-to-long period on what overall rate of local pulmonary tumour eradication the RFA treatment will settle. Obviously this is not the only parameter which affects efficacy of RFA. Many others will be taken into consideration, with particular attention to the RFA protocol and the technology utilised. Herrera et al. [12] treated a mixed cohort of 18 patients (5 via thoracotomy and 13 percutaneously) with primary and metastatic lung tumours. They utilised a needle electrode with multiple tines deployable into the tumour for 2 or 4 cm. At a mean follow-up period of 6 months, they reported a 55% complete or partial response rate and a 17% stable disease rate in lesions with a mean diameter of 5.3 cm. As happened in our experience, the response rates seemed to be better for smaller lesions (66% for lesions smaller than 5 cm vs 33% for lesions larger than 5 cm). Another important issue which arose in this paper was the contraindication to treat central lesions by RFA, due to the risk of fatal complications, as happened in one case in their experience. For this reason, our protocol, as well as that of other authors [13,17], provides that lesions must be at least 1 cm away from bigger airways and great vessels (i.e., those ilar or para-ilar). More recently, Fernando et al. [19] from the same institute reported an update of their experience selecting patients with primary NSCLC. Despite a longer follow-up period (14 months), the results were better than those of their preliminary experience (63% of complete ablation vs 55%). It seems that primary NSCLC is more responsive to RFA than is metastasis, which is in contrast with our findings. In our experience, in fact, even if there is no statistical significance, metastases have a better complete response rate than primary lung tumours. An explanation of this finding could be found in the different biological behaviour of NSCLC and lung metastases, with the seconds generally well delimitated from the surrounding lung parenchyma, on the contrary of primary lung cancer that is often speculate and microscopically invading the lymphatic vessels around the macroscopic lesion. Moreover, in our experience, the better survival in case of metastases from extra-thoracic malignancies may be the result of a very accurate selection of the patients that were required to have the primary cancer cured and no other site of the disease.
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Currently, to our knowledge, there is no other study that reports the effect of RFA on pulmonary function. In our experience, spirometry performed before and after RFA at several intervals shows a slight reduction of FVC and FEV1 in the 1st month (however not statistically significant), which is promptly recovered at the 3rd month.
In conclusion, if the feasibility and safety of RFA in lung tumours have been assessed, its efficacy still remains to be determined, above all in the mid-to-long period. So, well-designed clinical trials with a long-term follow-up are required to confirm the short-term of the literature and our mid-term results, before RFA can enter into clinical practice. From the first experiences, as it was expected, it seems to be more effective for lesions smaller than 3 cm and, in our experience, for metastases. Certainly, it is necessary to underline the purpose of RFA, which regards only the local treatment of the tumour, with all its limits. In fact, if compared with surgical resection, despite a successful RFA, a higher recurrence rate is expected, locally and in the mediastinum. And, just as wedge resection is considered a compromise operation in respect to lobectomy for NSCLC, RFA may be considered a compromise procedure in respect to surgical resection for pulmonary tumours (primary or metastatic) in high-risk patients. In future, it would be of interest to compare RFA with other emerging alternative therapies (i.e., stereotactic radiosurgery), respect to quality of life, tumour control and survival.
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Appendix A |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Dr P. Macchiarini (Barcelona, Spain): You said that the indication are surgical contraindication, but you still have nine patients that for some reason were operated thereafter, so could you explain on that.
Dr Lucchi : Those nine cases were part of the first protocol. We explained to the patients what we were going to do and they accepted. Those were not surgical contraindication, but we did it to verify that there was a sense to the radiofrequency ablation. Otherwise we stuck with our study.
Dr G. Friedel (Gerlingen, Germany): And in those patients you did, in all, did you find a complete response histologically?
Dr Lucchi : No, only six of nine, that means about 60%.
Dr R. Rami-Porta (Barcelona, Spain): My question is technical. The duration of treatment ranged from 15 to 27 min. So how did you determine the duration of the heating?
Dr Lucchi : The length of the treatment is determined on the size of the tumour, on the diameter, and on the temperature that is monitored by the instrument. The range 15–27 min is the time at the target temperature of 90 °C. To this time you have to add that necessary to reach the target temperature.
Dr D. Branscheid (Grosshansdorf, Germany): I’d like to read something out of your abstract. The last sentence, ‘must be considered an alternative local therapy only when surgery cannot be performed.’
I missed that here in the conclusions. And I think it's highly experimental. We are just finding out that complete resection, surgical resection of metastasis, gives a better survival. We have fought to use laser resection, and we do not say that laser is better than conservative.
Might it probably be that you meant with your conclusion that could be an additive to our strategy in metastasis, perhaps in the future, when we do not come along with laser and with conventional resections?
Dr Lucchi : I agree with your consideration. We are all thoracic surgeons, so surgery remains the first choice in most of the cases; also for metastasis, when oncologist propose patients to us.
In any case, there are some patients who also for metastasis are not anymore indicated to surgical operation. And in reason of a so low morbidity, and maybe, as I observed, good results, also radiofrequency ablation may have a role. Moreover, in some cases, I think that hyperthermia, induced by radiofrequency ablation, may enhance the power of radiotherapy and also of chemotherapy.
Dr S. Mattioli (Bologna, Italy): I am interested in the last sentence of your conclusions. Would you apply first radiofrequency and secondly radiotherapy, stereotactic radiotherapy, or vice versa?
Dr Lucchi : What we know is that hyperthermia is the best radio-sensitizing. So there could be a rationale to do radiofrequency ablation and then radiotherapy.
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Footnotes |
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Presented at the joint 19th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 13th Annual Meeting of the European Society of Thoracic Surgeons, Barcelona, Spain, September 25–28, 2005. |
References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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