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CT to assess response to radiofrequency ablation of lung metastases
Rev Esp Med Nucl Imagen Mol. 2016;35(4):226–231
Original article
Dual time-point 18 F-FDG PET/CT to assess response to radiofrequency ablation of lung metastases S. Lafuente a , D. Fuster a,∗ , P. Arguis b , U. Granados a , P. Perlaza a , P. Paredes a , I. Vollmer b , ˜ a M. Sánchez b , F. Lomena a b
Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain Radiology Department, Hospital Clínic, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 11 November 2015 Accepted 14 December 2015 Available online 2 February 2016 Keywords: PET/CT Delayed images Radiofrequency Lung metastases Gastrointestinal cancer
a b s t r a c t Aim: To establish the usefulness of dual time-point PET/CT imaging in determining the response to radiofrequency ablation (RFA) of solitary lung metastases from gastrointestinal cancer. Materials and methods: This prospective study included 18 cases (3 female, 15 male, mean age 71 ± 15 yrs) with solitary lung metastases from malignant digestive tract tumors candidates for RFA. PET/CT images 1 h after injection of 4.07 MBq/kg of 18 F-FDG (standard images) were performed at baseline, 1 month, and 3 months after RFA. PET/CT images 2 h after injection centered in the thorax at 1 month after RFA were also performed (delayed images). A retention index (RI) of dual time-point images was calculated as follows: RI = (SUVmax delayed image − SUVmax standard image/SUVmax standard image) * 100. Pathological confirmation of residual tumor by histology of the treated lesion was considered as local recurrence. A negative imaging follow-up was considered as complete response. Results: Local recurrence was found in 6/18 lesions, and complete response in the remaining 12. The mean percentage change in SUVmax at 1 month and at 3 months showed a sensitivity and specificity for PET/CT of 50% and 33%, and 67% and 92%, respectively. The RI at 1 month after RFA showed a sensitivity and specificity of 83% and 92%, respectively. Conclusions: Dual time point PET/CT can predict the outcome at one month after RFA in lung metastases from digestive tract cancers. The RI can be used to indicate the need for further procedures to rule out persistent tumor due to incomplete RFA. ˜S.L.U. Elsevier Espana, S.L.U. © 2015 © 2015 Elsevier España, andy SEMNIM. All rights reserved.
Imágenes en 2 tiempos con 18 F-FDG PET/TC para evaluar la ablación por radiofrecuencia de las metástasis pulmonares r e s u m e n Palabras clave: PET/TC Imágenes tardías Radiofrecuencia Metástasis pulmonares Cáncer digestivo
Objetivo: Establecer la utilidad de las imágenes PET/TC en 2 tiempos en la determinación de la respuesta a la ablación por radiofrecuencia (RFA) de las metástasis pulmonares de tumores digestivos. ˜ Material y métodos: Estudio prospectivo con 18 casos (3 mujeres, 15 varones) y edad media de 71 ± 15 anos con metástasis pulmonar única de cáncer digestivo candidato a tratamiento mediante RFA. Se realizaron imágenes PET/CT 1 h tras inyección de 4,07 MBq/Kg de 18 F-FDG (imagen estándar) basal, un mes y 3 meses después de la RFA y una imagen tardía 2 h tras la inyección centrada en tórax un mes después de la RFA. Se calculó el índice de retención (RI): RI = (SUVmáx imagen tardía − SUVmáx imagen estándar/SUVmáx imagen estándar) * 100. La recurrencia local se confirmó con estudio histológico de la lesión tratada con RFA. Un resultado negativo en las pruebas de imagen durante el seguimiento se consideró como respuesta completa. Resultados: Se diagnosticó recidiva local en 6/18 lesiones y respuesta completa en 12/18. El cambio porcentual medio de SUVmáx al mes y a los 3 meses mostró una sensibilidad y especificidad para evaluar la respuesta a la RFA de 50% y 33% y 67% y 92%, respectivamente. El RI un mes posradiofrecuencia mostró una sensibilidad y especificidad del 83% y 92%. Conclusiones: Las imágenes en 2 tiempos con PET/TC un mes posradiofrecuencia pueden predecir el resultado de la RFA de las metástasis pulmonares de origen digestivo. El RI se puede utilizar para indicar la necesidad de otros procedimientos para descartar recurrencia tumoral debido a una RFA incompleta. ˜ S.L.U. y SEMNIM. Todos los derechos reservados. © 2015 Elsevier Espana,
∗ Corresponding author. E-mail address: [email protected] (D. Fuster). http://dx.doi.org/10.1016/j.remn.2015.12.002 ˜ S.L.U. 2253-8089/© 2015 2015 Elsevier SEMNIM.All Allrights rightsreserved. reserved. ElsevierEspaña, Espana, S.L.U.and y SEMNIM. 2253-654X/©
S. Lafuente et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(4):226–231
Introduction
Materials and methods
Surgical removal is the treatment of choice for lung metastases in those patients with solitary lesions and no evidence of extra-thoracic recurrence.1 Non-operable patients, due to poor clinical performance and/or the location of the lung metastases (central lesions, close to great vessels, etc.) can undergo chemotherapy with or without radiotherapy which, although associated with a worse prognosis, has been shown to improve survival outcome.2,3 Recently, thermal ablation using radiofrequency (RFA) has been used on isolated lung metastases, provoking an intense local inflammatory reaction around the metastasis and resulting in a complete healing in a high percentage of cases.4 According to Gillams et al., in lesions below 3 cm in size a success rate of 100% has been reported with a significant improvement in overall survival.5 The risk of recurrence or incomplete treatment after RFA is described as between 8% and 55% depending on the series and on the size of the lesion, location of the lung metastasis, duration of follow-up and the diagnostic method used. The lesion shows up on CT as an opaque area surrounding the treated zone,5,6 making it difficult to differentiate persistent disease or incomplete treatment of the metastasis from RFA-induced inflammation. In the majority of cases, treated lesions do not start to decrease in size until 3 weeks after treatment6–7 and it is not unusual to see an inflammation-induced size increase over the first 3 months.4,8,9 Furthermore, contrast-MRI is not easy to interpret although promising results have been obtained using diffusionMRI.10 18 F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), especially when combined with CT (PET/CT), has shown itself to be the best non-invasive imaging technique for evaluating tumor response to both chemotherapy and radiotherapy in the treatment of various malignant tumors.11 It allows an accurate detection of residual disease or secondary changes due to surgery.12 Certain difficulties may arise, however, when interpreting uptake in the presence of important inflammatory activity, which is the case in RFA of lung metastases. Several false positives have been described in circumstances where an infectious or inflammatory process was present,13 so to distinguish malignant from benign uptake SUVmax alone cannot be considered a reliable indicator. Complications associated with RFA, such as infections and abscess formation, can also be a potential source of false positive findings on PET/CT. Knowledge of the morphologic imaging features of these complications as well as awareness of their clinical manifestations is important to avoid potential pitfalls. This problem has also been reported in liver tumors treated with RFA for which inflammatory uptakes were maximal at an early stage.6,8 Studies in the literature have focused on differential diagnosis of benign and malignant lesions by performing multiple time-point images. It has been suggested that late images can help in this respect.14 Kumar et al. have shown that both benign and malignant breast cancer tumors behave in the same manner during the first hour of image acquisition, which can lead to diagnostic errors. In later images, however, malignant tumors show a significant increase in uptake, whilst uptake in inflammatory lesions decreases considerably.15 Considering the difficulties of anatomic procedures as well as standard quantification with PET/CT to differentiate between therapyinduced inflammatory changes and persistence of malignancy, it is relevant to evaluate if dual time point may improve current results. The aim of this study was to establish the usefulness of dual time-point PET/CT imaging in determining the response to RFA of solitary lung metastases from digestive cancer.
Patients
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This prospective study comprised 18 patients (3 women, 15 men) with a mean age of 71 ± 15 years with solitary lung metastases from digestive malignant tumors not eligible for surgical resection and candidates for RFA (see Table 1). Patients were evaluated using standard procedures to exclude other sites of tumoral activity before their inclusion in the study. The gold standard was histologic confirmation of active tumor with fine needle aspiration or biopsy of the treated lesion (persistent tumor). A negative imaging follow-up was considered as complete response (median follow-up 15 months, range 5–24 months). The Hospital’s Ethics Committee approved the study and all patients gave their informed written consent. Radiofrequency ablation RFA was performed using a CT fluoroscopy guide to place the electrode in the tumors. The electrodes used for the ablation included a multitined expandable electrode (LeVeen, Boston Scientific) and a single internally cooled electrode (Cool-tip, Valleylab). The procedures were performed with the patients under conscious sedation (via administration of remifentanil) and local anesthesia (2% mepivacaine). The patient’s vital signs were non-invasively monitored throughout. A chest CT scan was performed immediately and 24 h after the procedure to evaluate the ablation zone and check for procedural complications such as lung bleeding, pneumothorax, hemothorax, or pleural effusion. PET/CT acquisition protocol Whole-body PET/CT at 1 h (standard images) post-injection of 4.07 MBq/kg (0.11 mCi/kg) of FDG was performed at baseline, 1 month and 3 months post-RFA. PET/CT images centered in the thorax were obtained 2 h after injection at 1-month post-RFA in all patients (delayed images). A hybrid PET/CT system (Biograph, Siemens) that incorporates a low-dose helical CT scanner (Somatom, Emotion) was used. Patients fasted for 6 h prior to PET acquisition. Blood glucose levels were required to be less than 140 mg/dl. Patients were allowed to breathe normally during PET and CT acquisitions. During acquisitions, patients were in supine position with their arms raised above the head. Wholebody PET data were acquired in three-dimensional mode and for 4 min per bed position. PET images were reconstructed using CT data for attenuation correction, using the ordered-subsets expectation maximization algorithm and without CT-based attenuation correction. A low-dose chest CT was performed under apnea conditions immediately after the PET/CT, using an AP tube, craniocaudal, 50 mA, 130 kV, scan time 55 s, and thickness 5–8 mm. For patients weighing more than 80 kg, the intensity was raised to 90 mA. Criteria for evaluation A region of interest around the tumor was placed manually in transaxial, sagittal and coronal slices to calculate SUVmax . The mean percentage change of SUVmax (SUVmax ) at 1 month and 3 months was used to evaluate metabolic response of FDG PET. Dual time-point images were evaluated using the retention index (RI), defined as follows: RI = (SUVmax delayed image − SUVmax standard image/SUVmax standard image) * 100.16,17
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Table 1 Patients characteristics and imaging data. Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Primary tumor
Sigmoid Right colon Sigmoid Left colon Rectum Gallbladder Right colon Rectum Right colon Sigmoid Rectum Sigmoid Sigmoid Left colon Sigmoid Rectum Pancreas Right colon
Baseline
Size (cm)
Age
Gender
Location
73 74 76 73 67 81 84 90 85 80 56 64 66 77 77 75 33 60
Male Male Female Female Male Male Male Male Male Male Female Male Male Male Male Male Male Male
RLL LIL RUL LLL LIL RLL LLL LUL LUL ML LLL LLL LLL RLL RUL LUL RLL LLL
1.7 1.5 1.6 1.1 2.5 1.1 2.2 1.9 2.6 2.1 1 2.3 4.5 1.6 2.6 1.3 0.6 1.5
SUVmax
1.3 1.3 6.3 1.3 3.3 2.6 2.3 5.4 1.6 4.6 2.3 3 2.5 2.1 1.8 1.7 1.4 1.2
1 month
3 months
SUVmax (standard images)
SUVmax
SUVmax (delayed images)
Retention index (RI)
SUVmax
SUVmax
Response to RFA
2.3 1.5 1.8 2.2 2.2 2 2.3 1.6 2.2 2.9 1.2 1.5 2.2 1.1 1.2 1.8 1.3 1.1
76.9 15.4 −71.4 69.2 −33.3 −23.1 0 −70.4 37.5 −37 −47.8 −50 −12 −47.6 −33.3 5.9 −7.1 −8.3
2 1.1 1.9 2.4 2.8 2.1 2.2 3.1 2.3 2.3 1.5 1.8 2.7 1.4 1.3 1.8 1.2 1.1
−13 −26.7 5.6 9.1 27.3 5 −4.3 93.8 4.5 −20.7 25 20 22.7 27.3 8.3 0 −7.7 0
2.3 1.4 1.8 2.5 4.3 1.5 1.6 1.6 1.7 2.4 3.7 1.3 2.9 1.9 1.5 1.6 1.1 1
76.9 7.7 −71.4 92.3 30.3 −42.3 −30.4 −70.4 6.3 −47.8 60.9 −56.7 16 −9.5 −16.7 −5.9 −21.4 −16.7
PT CR CR CR PT CR CR PT CR CR PT PT PT CR CR CR CR CR
RUL: right upper lobe; ML: middle lobe; RLL: right lower lobe; LUL: left upper lobe; LLL: left lower lobe; SUVmax = variations in SUVmax ; RFA: radiofrequency ablation; PT: persistent tumor; CR: complete response.
Statistical analysis Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. ROC curves for SUVmax at 1- and 3-month images and RI between 1- and 2-h measurements on the 1-month image were developed to establish the optimal cut-off that discriminates between local recurrence and complete response for PET/CT (Package pROC). The cut-off was computed to minimize the Youden’s index. A Mann–Whitney U test was used to assess differences between groups with p-values < 0.05 considered statistically significant.
Regarding the 6 patients with disease progression, 5 were found to have also recurrence at the RFA lesion site. One of the patients developed adrenal metastases, three showed liver metastases and two patients showed new pulmonary metastases away from the treated lesions with RFA. We found only one false negative case and one case of a false positive using the RI. In the false positive case, the primary tumor was from left colon, and interestingly, the SUVmax decreased from a baseline SUVmax of 2.1 to virtually background activity of only 1.1 at 1 month, before increasing to 1.7 at 3 months after RFA (RI = 37%). The false negative case was a sigma primary tumor with a baseline SUVmax of 1.7 and a SUVmax of 2.3 at 1 month and 3 months (RI = −13%).
Results
Discussion
The mean size of target lung metastases at baseline was 1.86 ± 0.8 cm and all lesions showed FDG uptake greater than background at baseline (mean SUVmax = 2.56 ± 1.4). We found persistent tumor in 6/18 lesions (Fig. 1) and a complete response in the remaining 12/18. In 3 out of the 6 persistent tumor cases, the lung metastasis was adjacent to lung fissures, and in one case, nearby vessels made it impossible to carry out optimal treatment. There was no association between age, sex, primary tumor, lobar location of the lung metastases, lesion size or SUVmax at baseline and the response to radiofrequency ablation (Mann–Whitney U test, p > 0.05). The sensitivity, specificity, PPV and NPV for PET/CT are described in Tables 2 and 3. ROC curves analysis showed that the best SUVmax thresholds to differentiate between complete response and persistent tumor with PET/CT at 1 month and 3 months after RFA were −28% and 16%, respectively. The RI calculated using dual time-point images at 1 month after RFA showed higher sensitivity and specificity than standard SUVmax at 1 month after RFA of 83% and 92% versus 50% and 33%. The sensitivity was also higher than standard SUVmax at 3 month after RFA (67%) with the same specificity (Table 3). The best threshold using the ROC curves for RI at 1 month was 17%. As can be seen from the developed ROC curves, the RI at 1 month is the most appropriate parameter to establish response to RFA with PET/CT (Fig. 2).
Treatment of non-operable solitary lung metastases using percutaneous RFA has showed itself to be a valid therapeutic option for recurrent digestive cancer, with survival rates similar to other non-surgical options such as chemotherapy and/or radiotherapy.18 Nonetheless, the treatment can be unsuccessful in up to 55% of cases.5,6 One of the issues of this technique is that when lesions are highly vascularized due to the cooling effect of circulating blood, the effectiveness of RFA can be reduced. Other bad prognostic indicators of recurrence after RFA should include a lung metastasis size of more than 3 cm and lesions close to blood vessels. In our series, only one patient could not receive optimal RFA treatment due to the proximity of blood vessels. However, in 3 out of the 6 recurrences, the lung metastasis was adjacent to either mediastinum or pleura, suggesting its potential to interfere with the correct administration of RFA.5 RFA-induced changes are currently evaluated using CT or MRI, but the intense inflammation caused by RFA in the treated metastatic lesion and adjoining tissue can result in incorrect evaluation of the presence of remaining tumor and/or early recurrence after treatment. The problems experienced by anatomical imaging techniques can also affect PET/CT, making metabolic monitoring of the treated lesion difficult until at least 3 months after the ablative procedure. This is often a too long delay to allow curative retreatment of recurrence if it has spread to other extra-thoracic sites.5 According to our results, SUVmax changes at 1 month post-
S. Lafuente et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(4):226–231
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Fig. 1. PET/CT at baseline (A), at 1 month (B) and at 3 months (C) after radiofrequency ablation of a lung metastasis located in the left lower lobe. The SUVmax at 1 month was −33.3 suggesting inflammation changes. However, the RI at 1 month (standard (B) and delayed (D) images) and the SUVmax at 3 months after treatment were 27.3% and 30.3%, indicating persistent tumor in the treated lung metastasis. Table 2 Results obtained with SUVmax on PET/CT at 1 month and at 3 month after RFA. PET/CT 1 month after RFA Complete response SUVmax ≤ 28% 4 SUVmax > 28% 8 Total 12 Optimal threshold = −28 CI95% (−158.61, 63.37)
Persistent tumor
Total
3 3 6
7 11 18
Sensitivity Specificity PPV NPP
50% 33% 27% 57%
Sensitivity Specificity PPV NPP
67% 92% 80% 85%
PET/CT 3 months after RFA Complete response SUVmax ≤ 16% 11 1 SUVmax > 16% 12 Total Optimal threshold = 16 CI95% (−39.89, 71.89)
Persistent tumor
Total
2 4 6
13 5 18
Table 3 Results obtained with the RI on PET/CT at 1 month after RFA. Complete response RI ≤ 17% 11 RI > 17% 1 12 Total Optimal threshold = 17 CI95%: (6.11, 27.23)
Persistent tumor
Total
1 5 6
12 6 18
RFA when compared with basal PET prior to RFA showing poor results, with a sensitivity of 50% and an even lower specificity of 33%. Bonichon et al., found PET/CT useful regarding its negative predictive value at 3 months post-RFA, but positive findings need to be confirmed due to false positive results.19 Interestingly, we found that sensitivity of PET/CT at 3 months post-RFA was still suboptimal (67%), but with a very good specificity and NPV values of 92% and 85%, indicating that it would be a suitable parameter for the diagnosis of disease persistence.
Sensitivity Specificity PPV NPP
83% 92% 83% 92%
Deandreis et al.20 demonstrated that PET/CT can depict a higher number of treatment failures than chest CT, earlier and without any cases of false-negative findings. In particular, PET alone depicted cases of incomplete treatment (3 out of 3) that were not detected by chest CT, as early as 1 month after RFA. However, according to our results, specificity of PET/CT at 1 month post-RFA is low showing values of only 58%. At an early stage, the relapsed lesion is often small in diameter and is embedded inside the ablation zone without visible changes in morphologic aspect and/or contrast
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ROC curves 1.0
True positive rate
0.8
0.6
0.4
0.2 ΔSUVmax (1 mo) ΔSUVmax (3 mo) RI (3 mo)
0.0 0.0
0.2
0.4
0.6
0.8
1.0
False positive rate Fig. 2. ROC curves analysis of PET/CT using the RI at 1 month and SUVmax at 1 month and 3 months after radiofrequency ablation.
enhancement. Moreover, the number of inflammatory uptakes on FDG PET is also high at early stages after RFA.21 Zhuang et al. observed in a study with mice that activity curves of 18 F-FDG in inflammatory lesions varied, with a rise in the first hour followed by a progressive decline. In contrast, tumor lesions showed an upward activity curve right from the start, stabilizing at a maximum at 2 h post-injection.18 Lin et al. do not support the routine use of dual time-point imaging with FDG PET in the differential diagnosis of pulmonary nodules.22 However, they suggest that PET may provide additional information in specific cases with equivocal results from initial scanning. Contrast-enhanced CT demonstrated the lowest accuracy levels and they concluded that dual time-point PET imaging was the most sensitive, whereas initial PET imaging was the most specific. In our series, changes in SUVmax between standard and delayed images using the RI at 1 month postRFA showed a sensitivity and PPV of 83%, with high specificity and NPV of 92%. These results suggest that PET/CT is able to provide an earlier detection of cases where RFA treatment has not been successful, allowing prompt retreatment of the lesions. Despite the small number of cases in this study, results would indicate that dual time point may be useful in monitoring these patients. The RI has been used in the diagnostic of liver or lung metastases by other authors using a threshold of 10%13,15,22–24 which is similar to the threshold obtained in this study using the ROC curves (17%). In a previous work of our group using PET/CT in operated colorectal cancer, the results showed that delayed images were able to significantly diagnose a higher number of liver metastases (66/79) compared to standard images (57/79).24 Nilendu et al. evaluated the role of FDG PET in assessing the response of lesions to RFA. Surveillance with FDG PET examinations performed serially can be used for early diagnosis of recurrence.25 It should be noted, however, that the use of FDG PET for the monitoring and surveillance of lung lesions is not yet well established, and exact time points for follow-up imaging are yet to be defined. Further work based on the promising findings from pilot studies will be needed to ensure the early detection of recurrence and progressive disease, which can give the patient an opportunity to be treated with alternative therapies. Focusing in the progression of the disease, two different situations may occur, the appearance of disease away from the treated lung metastasis after complete response to RFA or both distant disease and a progression of the
treated lesion. Actually, 5 out of the 6 cases of disease progression seen on follow-up also showed a local recurrence of the treated lung metastasis. In cases where disease progression was found after incomplete response of the treated lesion to RFA, an earlier detection of incomplete treatment would have probably improved survival in these patients who are no longer candidates for locally curative therapeutic options. In summary, monitoring of the RF-treated lesion is actually difficult, until at least 3 months after the ablative procedure, and a too long delay for retreatment of recurrence may be a loss of chance for the patient. Investigating whether FDG PET-CT dual time-point can show persistence of malignancy as early as possible is relevant. In addition, there is still limited data in the literature to establish the role of PET/CT in the follow-up of RFA of lung metastases. To our knowledge, this is the first study using dual time point at 1 month after RFA of lung metastases showing better results than standard variations on SUVmax at 3 months after treatment. These results indicate that using dual time point images at 1 month we could earlier detect the persistence of tumor due to incomplete RFA, or it could prevent the progression of the disease with more efficacy than the standard methods currently used. Conclusion In conclusion, dual time-point images with PET/CT at one month after RFA show better results than standard PET/CT in patients with solitary lung metastases from digestive cancer. The results indicate that the retention index obtained with dual time-point PET/CT at one month is more appropriate than SUVmax changes to detect persistent tumor in lung metastases treated with RFA, and, when this is the case, further procedures should be performed to rule out malignancy due to incomplete treatment. Conflict of interest The authors declare no conflicts of interest. Acknowledgement This work was supported by AGAUR 2014 SGR 279. References 1. Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, et al. The International Registry of Lung Metastases. Long-term results of lung metastasectomy prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg. 1997;113:37–49. 2. Yan TD, King J, Sjarif A, Glenn D, Steinke K, Morris DL. Percutaneous radiofrequency ablation of pulmonary metastases from colorectal carcinoma: prognostic determinants for survival. Ann Surg Oncol. 2006;13:1529–37. 3. Tampellini M, Ottone A, Bellini E, Alabiso I, Baratelli C, Bitossi R, et al. The role of lung metastasis resection in improving outcome of colorectal cancer patients: results from a large retrospective study. Oncologist. 2012;17:1430–8. 4. De Baère T, Palussière J, Aupérin A, Hakime A, Abdel-Rehim M, Kind M, et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: prospective evaluation. Radiology. 2006;240:587–96. 5. Gillams AR, Lees WR. Radiofrequency ablation of lung metastases: factors influencing success. Eur Radiol. 2008;18:672–7. 6. De Baère T. Lung tumor radiofrequency ablation: where do we stand. Cardiovasc Intervent Radiol. 2011;34:424–30. 7. Tominaga J, Miyachi H, Takase K, Matsuhashi T, Yamada T, Sato A, et al. Timerelated changes in computed tomographic appearance and pathologic findings after radiofrequency ablation of the rabbit lung: preliminary experimental study. J Vasc Interv Radiol. 2005;16:1719–26. 8. Anderson EM, Lees WR, Gillams AR. Early indicators of treatment success after percutaneous radiofrequency of pulmonary tumors. Cardiovasc Intervent Radiol. 2009;32:478–83. 9. Bojarski JD, Dupuy DE, Mayo-Smith WW. CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: results in 32 tumors. AJR Am J Roentgenol. 2005;185:466–71.
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Original article
Dual time-point 18 F-FDG PET/CT to assess response to radiofrequency ablation of lung metastases S. Lafuente a , D. Fuster a,∗ , P. Arguis b , U. Granados a , P. Perlaza a , P. Paredes a , I. Vollmer b , ˜ a M. Sánchez b , F. Lomena a b
Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain Radiology Department, Hospital Clínic, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 11 November 2015 Accepted 14 December 2015 Available online 2 February 2016 Keywords: PET/CT Delayed images Radiofrequency Lung metastases Gastrointestinal cancer
a b s t r a c t Aim: To establish the usefulness of dual time-point PET/CT imaging in determining the response to radiofrequency ablation (RFA) of solitary lung metastases from gastrointestinal cancer. Materials and methods: This prospective study included 18 cases (3 female, 15 male, mean age 71 ± 15 yrs) with solitary lung metastases from malignant digestive tract tumors candidates for RFA. PET/CT images 1 h after injection of 4.07 MBq/kg of 18 F-FDG (standard images) were performed at baseline, 1 month, and 3 months after RFA. PET/CT images 2 h after injection centered in the thorax at 1 month after RFA were also performed (delayed images). A retention index (RI) of dual time-point images was calculated as follows: RI = (SUVmax delayed image − SUVmax standard image/SUVmax standard image) * 100. Pathological confirmation of residual tumor by histology of the treated lesion was considered as local recurrence. A negative imaging follow-up was considered as complete response. Results: Local recurrence was found in 6/18 lesions, and complete response in the remaining 12. The mean percentage change in SUVmax at 1 month and at 3 months showed a sensitivity and specificity for PET/CT of 50% and 33%, and 67% and 92%, respectively. The RI at 1 month after RFA showed a sensitivity and specificity of 83% and 92%, respectively. Conclusions: Dual time point PET/CT can predict the outcome at one month after RFA in lung metastases from digestive tract cancers. The RI can be used to indicate the need for further procedures to rule out persistent tumor due to incomplete RFA. ˜S.L.U. Elsevier Espana, S.L.U. © 2015 © 2015 Elsevier España, andy SEMNIM. All rights reserved.
Imágenes en 2 tiempos con 18 F-FDG PET/TC para evaluar la ablación por radiofrecuencia de las metástasis pulmonares r e s u m e n Palabras clave: PET/TC Imágenes tardías Radiofrecuencia Metástasis pulmonares Cáncer digestivo
Objetivo: Establecer la utilidad de las imágenes PET/TC en 2 tiempos en la determinación de la respuesta a la ablación por radiofrecuencia (RFA) de las metástasis pulmonares de tumores digestivos. ˜ Material y métodos: Estudio prospectivo con 18 casos (3 mujeres, 15 varones) y edad media de 71 ± 15 anos con metástasis pulmonar única de cáncer digestivo candidato a tratamiento mediante RFA. Se realizaron imágenes PET/CT 1 h tras inyección de 4,07 MBq/Kg de 18 F-FDG (imagen estándar) basal, un mes y 3 meses después de la RFA y una imagen tardía 2 h tras la inyección centrada en tórax un mes después de la RFA. Se calculó el índice de retención (RI): RI = (SUVmáx imagen tardía − SUVmáx imagen estándar/SUVmáx imagen estándar) * 100. La recurrencia local se confirmó con estudio histológico de la lesión tratada con RFA. Un resultado negativo en las pruebas de imagen durante el seguimiento se consideró como respuesta completa. Resultados: Se diagnosticó recidiva local en 6/18 lesiones y respuesta completa en 12/18. El cambio porcentual medio de SUVmáx al mes y a los 3 meses mostró una sensibilidad y especificidad para evaluar la respuesta a la RFA de 50% y 33% y 67% y 92%, respectivamente. El RI un mes posradiofrecuencia mostró una sensibilidad y especificidad del 83% y 92%. Conclusiones: Las imágenes en 2 tiempos con PET/TC un mes posradiofrecuencia pueden predecir el resultado de la RFA de las metástasis pulmonares de origen digestivo. El RI se puede utilizar para indicar la necesidad de otros procedimientos para descartar recurrencia tumoral debido a una RFA incompleta. ˜ S.L.U. y SEMNIM. Todos los derechos reservados. © 2015 Elsevier Espana,
∗ Corresponding author. E-mail address: [email protected] (D. Fuster). http://dx.doi.org/10.1016/j.remn.2015.12.002 ˜ S.L.U. 2253-8089/© 2015 2015 Elsevier SEMNIM.All Allrights rightsreserved. reserved. ElsevierEspaña, Espana, S.L.U.and y SEMNIM. 2253-654X/©
S. Lafuente et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(4):226–231
Introduction
Materials and methods
Surgical removal is the treatment of choice for lung metastases in those patients with solitary lesions and no evidence of extra-thoracic recurrence.1 Non-operable patients, due to poor clinical performance and/or the location of the lung metastases (central lesions, close to great vessels, etc.) can undergo chemotherapy with or without radiotherapy which, although associated with a worse prognosis, has been shown to improve survival outcome.2,3 Recently, thermal ablation using radiofrequency (RFA) has been used on isolated lung metastases, provoking an intense local inflammatory reaction around the metastasis and resulting in a complete healing in a high percentage of cases.4 According to Gillams et al., in lesions below 3 cm in size a success rate of 100% has been reported with a significant improvement in overall survival.5 The risk of recurrence or incomplete treatment after RFA is described as between 8% and 55% depending on the series and on the size of the lesion, location of the lung metastasis, duration of follow-up and the diagnostic method used. The lesion shows up on CT as an opaque area surrounding the treated zone,5,6 making it difficult to differentiate persistent disease or incomplete treatment of the metastasis from RFA-induced inflammation. In the majority of cases, treated lesions do not start to decrease in size until 3 weeks after treatment6–7 and it is not unusual to see an inflammation-induced size increase over the first 3 months.4,8,9 Furthermore, contrast-MRI is not easy to interpret although promising results have been obtained using diffusionMRI.10 18 F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), especially when combined with CT (PET/CT), has shown itself to be the best non-invasive imaging technique for evaluating tumor response to both chemotherapy and radiotherapy in the treatment of various malignant tumors.11 It allows an accurate detection of residual disease or secondary changes due to surgery.12 Certain difficulties may arise, however, when interpreting uptake in the presence of important inflammatory activity, which is the case in RFA of lung metastases. Several false positives have been described in circumstances where an infectious or inflammatory process was present,13 so to distinguish malignant from benign uptake SUVmax alone cannot be considered a reliable indicator. Complications associated with RFA, such as infections and abscess formation, can also be a potential source of false positive findings on PET/CT. Knowledge of the morphologic imaging features of these complications as well as awareness of their clinical manifestations is important to avoid potential pitfalls. This problem has also been reported in liver tumors treated with RFA for which inflammatory uptakes were maximal at an early stage.6,8 Studies in the literature have focused on differential diagnosis of benign and malignant lesions by performing multiple time-point images. It has been suggested that late images can help in this respect.14 Kumar et al. have shown that both benign and malignant breast cancer tumors behave in the same manner during the first hour of image acquisition, which can lead to diagnostic errors. In later images, however, malignant tumors show a significant increase in uptake, whilst uptake in inflammatory lesions decreases considerably.15 Considering the difficulties of anatomic procedures as well as standard quantification with PET/CT to differentiate between therapyinduced inflammatory changes and persistence of malignancy, it is relevant to evaluate if dual time point may improve current results. The aim of this study was to establish the usefulness of dual time-point PET/CT imaging in determining the response to RFA of solitary lung metastases from digestive cancer.
Patients
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This prospective study comprised 18 patients (3 women, 15 men) with a mean age of 71 ± 15 years with solitary lung metastases from digestive malignant tumors not eligible for surgical resection and candidates for RFA (see Table 1). Patients were evaluated using standard procedures to exclude other sites of tumoral activity before their inclusion in the study. The gold standard was histologic confirmation of active tumor with fine needle aspiration or biopsy of the treated lesion (persistent tumor). A negative imaging follow-up was considered as complete response (median follow-up 15 months, range 5–24 months). The Hospital’s Ethics Committee approved the study and all patients gave their informed written consent. Radiofrequency ablation RFA was performed using a CT fluoroscopy guide to place the electrode in the tumors. The electrodes used for the ablation included a multitined expandable electrode (LeVeen, Boston Scientific) and a single internally cooled electrode (Cool-tip, Valleylab). The procedures were performed with the patients under conscious sedation (via administration of remifentanil) and local anesthesia (2% mepivacaine). The patient’s vital signs were non-invasively monitored throughout. A chest CT scan was performed immediately and 24 h after the procedure to evaluate the ablation zone and check for procedural complications such as lung bleeding, pneumothorax, hemothorax, or pleural effusion. PET/CT acquisition protocol Whole-body PET/CT at 1 h (standard images) post-injection of 4.07 MBq/kg (0.11 mCi/kg) of FDG was performed at baseline, 1 month and 3 months post-RFA. PET/CT images centered in the thorax were obtained 2 h after injection at 1-month post-RFA in all patients (delayed images). A hybrid PET/CT system (Biograph, Siemens) that incorporates a low-dose helical CT scanner (Somatom, Emotion) was used. Patients fasted for 6 h prior to PET acquisition. Blood glucose levels were required to be less than 140 mg/dl. Patients were allowed to breathe normally during PET and CT acquisitions. During acquisitions, patients were in supine position with their arms raised above the head. Wholebody PET data were acquired in three-dimensional mode and for 4 min per bed position. PET images were reconstructed using CT data for attenuation correction, using the ordered-subsets expectation maximization algorithm and without CT-based attenuation correction. A low-dose chest CT was performed under apnea conditions immediately after the PET/CT, using an AP tube, craniocaudal, 50 mA, 130 kV, scan time 55 s, and thickness 5–8 mm. For patients weighing more than 80 kg, the intensity was raised to 90 mA. Criteria for evaluation A region of interest around the tumor was placed manually in transaxial, sagittal and coronal slices to calculate SUVmax . The mean percentage change of SUVmax (SUVmax ) at 1 month and 3 months was used to evaluate metabolic response of FDG PET. Dual time-point images were evaluated using the retention index (RI), defined as follows: RI = (SUVmax delayed image − SUVmax standard image/SUVmax standard image) * 100.16,17
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Table 1 Patients characteristics and imaging data. Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Primary tumor
Sigmoid Right colon Sigmoid Left colon Rectum Gallbladder Right colon Rectum Right colon Sigmoid Rectum Sigmoid Sigmoid Left colon Sigmoid Rectum Pancreas Right colon
Baseline
Size (cm)
Age
Gender
Location
73 74 76 73 67 81 84 90 85 80 56 64 66 77 77 75 33 60
Male Male Female Female Male Male Male Male Male Male Female Male Male Male Male Male Male Male
RLL LIL RUL LLL LIL RLL LLL LUL LUL ML LLL LLL LLL RLL RUL LUL RLL LLL
1.7 1.5 1.6 1.1 2.5 1.1 2.2 1.9 2.6 2.1 1 2.3 4.5 1.6 2.6 1.3 0.6 1.5
SUVmax
1.3 1.3 6.3 1.3 3.3 2.6 2.3 5.4 1.6 4.6 2.3 3 2.5 2.1 1.8 1.7 1.4 1.2
1 month
3 months
SUVmax (standard images)
SUVmax
SUVmax (delayed images)
Retention index (RI)
SUVmax
SUVmax
Response to RFA
2.3 1.5 1.8 2.2 2.2 2 2.3 1.6 2.2 2.9 1.2 1.5 2.2 1.1 1.2 1.8 1.3 1.1
76.9 15.4 −71.4 69.2 −33.3 −23.1 0 −70.4 37.5 −37 −47.8 −50 −12 −47.6 −33.3 5.9 −7.1 −8.3
2 1.1 1.9 2.4 2.8 2.1 2.2 3.1 2.3 2.3 1.5 1.8 2.7 1.4 1.3 1.8 1.2 1.1
−13 −26.7 5.6 9.1 27.3 5 −4.3 93.8 4.5 −20.7 25 20 22.7 27.3 8.3 0 −7.7 0
2.3 1.4 1.8 2.5 4.3 1.5 1.6 1.6 1.7 2.4 3.7 1.3 2.9 1.9 1.5 1.6 1.1 1
76.9 7.7 −71.4 92.3 30.3 −42.3 −30.4 −70.4 6.3 −47.8 60.9 −56.7 16 −9.5 −16.7 −5.9 −21.4 −16.7
PT CR CR CR PT CR CR PT CR CR PT PT PT CR CR CR CR CR
RUL: right upper lobe; ML: middle lobe; RLL: right lower lobe; LUL: left upper lobe; LLL: left lower lobe; SUVmax = variations in SUVmax ; RFA: radiofrequency ablation; PT: persistent tumor; CR: complete response.
Statistical analysis Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. ROC curves for SUVmax at 1- and 3-month images and RI between 1- and 2-h measurements on the 1-month image were developed to establish the optimal cut-off that discriminates between local recurrence and complete response for PET/CT (Package pROC). The cut-off was computed to minimize the Youden’s index. A Mann–Whitney U test was used to assess differences between groups with p-values < 0.05 considered statistically significant.
Regarding the 6 patients with disease progression, 5 were found to have also recurrence at the RFA lesion site. One of the patients developed adrenal metastases, three showed liver metastases and two patients showed new pulmonary metastases away from the treated lesions with RFA. We found only one false negative case and one case of a false positive using the RI. In the false positive case, the primary tumor was from left colon, and interestingly, the SUVmax decreased from a baseline SUVmax of 2.1 to virtually background activity of only 1.1 at 1 month, before increasing to 1.7 at 3 months after RFA (RI = 37%). The false negative case was a sigma primary tumor with a baseline SUVmax of 1.7 and a SUVmax of 2.3 at 1 month and 3 months (RI = −13%).
Results
Discussion
The mean size of target lung metastases at baseline was 1.86 ± 0.8 cm and all lesions showed FDG uptake greater than background at baseline (mean SUVmax = 2.56 ± 1.4). We found persistent tumor in 6/18 lesions (Fig. 1) and a complete response in the remaining 12/18. In 3 out of the 6 persistent tumor cases, the lung metastasis was adjacent to lung fissures, and in one case, nearby vessels made it impossible to carry out optimal treatment. There was no association between age, sex, primary tumor, lobar location of the lung metastases, lesion size or SUVmax at baseline and the response to radiofrequency ablation (Mann–Whitney U test, p > 0.05). The sensitivity, specificity, PPV and NPV for PET/CT are described in Tables 2 and 3. ROC curves analysis showed that the best SUVmax thresholds to differentiate between complete response and persistent tumor with PET/CT at 1 month and 3 months after RFA were −28% and 16%, respectively. The RI calculated using dual time-point images at 1 month after RFA showed higher sensitivity and specificity than standard SUVmax at 1 month after RFA of 83% and 92% versus 50% and 33%. The sensitivity was also higher than standard SUVmax at 3 month after RFA (67%) with the same specificity (Table 3). The best threshold using the ROC curves for RI at 1 month was 17%. As can be seen from the developed ROC curves, the RI at 1 month is the most appropriate parameter to establish response to RFA with PET/CT (Fig. 2).
Treatment of non-operable solitary lung metastases using percutaneous RFA has showed itself to be a valid therapeutic option for recurrent digestive cancer, with survival rates similar to other non-surgical options such as chemotherapy and/or radiotherapy.18 Nonetheless, the treatment can be unsuccessful in up to 55% of cases.5,6 One of the issues of this technique is that when lesions are highly vascularized due to the cooling effect of circulating blood, the effectiveness of RFA can be reduced. Other bad prognostic indicators of recurrence after RFA should include a lung metastasis size of more than 3 cm and lesions close to blood vessels. In our series, only one patient could not receive optimal RFA treatment due to the proximity of blood vessels. However, in 3 out of the 6 recurrences, the lung metastasis was adjacent to either mediastinum or pleura, suggesting its potential to interfere with the correct administration of RFA.5 RFA-induced changes are currently evaluated using CT or MRI, but the intense inflammation caused by RFA in the treated metastatic lesion and adjoining tissue can result in incorrect evaluation of the presence of remaining tumor and/or early recurrence after treatment. The problems experienced by anatomical imaging techniques can also affect PET/CT, making metabolic monitoring of the treated lesion difficult until at least 3 months after the ablative procedure. This is often a too long delay to allow curative retreatment of recurrence if it has spread to other extra-thoracic sites.5 According to our results, SUVmax changes at 1 month post-
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Fig. 1. PET/CT at baseline (A), at 1 month (B) and at 3 months (C) after radiofrequency ablation of a lung metastasis located in the left lower lobe. The SUVmax at 1 month was −33.3 suggesting inflammation changes. However, the RI at 1 month (standard (B) and delayed (D) images) and the SUVmax at 3 months after treatment were 27.3% and 30.3%, indicating persistent tumor in the treated lung metastasis. Table 2 Results obtained with SUVmax on PET/CT at 1 month and at 3 month after RFA. PET/CT 1 month after RFA Complete response SUVmax ≤ 28% 4 SUVmax > 28% 8 Total 12 Optimal threshold = −28 CI95% (−158.61, 63.37)
Persistent tumor
Total
3 3 6
7 11 18
Sensitivity Specificity PPV NPP
50% 33% 27% 57%
Sensitivity Specificity PPV NPP
67% 92% 80% 85%
PET/CT 3 months after RFA Complete response SUVmax ≤ 16% 11 1 SUVmax > 16% 12 Total Optimal threshold = 16 CI95% (−39.89, 71.89)
Persistent tumor
Total
2 4 6
13 5 18
Table 3 Results obtained with the RI on PET/CT at 1 month after RFA. Complete response RI ≤ 17% 11 RI > 17% 1 12 Total Optimal threshold = 17 CI95%: (6.11, 27.23)
Persistent tumor
Total
1 5 6
12 6 18
RFA when compared with basal PET prior to RFA showing poor results, with a sensitivity of 50% and an even lower specificity of 33%. Bonichon et al., found PET/CT useful regarding its negative predictive value at 3 months post-RFA, but positive findings need to be confirmed due to false positive results.19 Interestingly, we found that sensitivity of PET/CT at 3 months post-RFA was still suboptimal (67%), but with a very good specificity and NPV values of 92% and 85%, indicating that it would be a suitable parameter for the diagnosis of disease persistence.
Sensitivity Specificity PPV NPP
83% 92% 83% 92%
Deandreis et al.20 demonstrated that PET/CT can depict a higher number of treatment failures than chest CT, earlier and without any cases of false-negative findings. In particular, PET alone depicted cases of incomplete treatment (3 out of 3) that were not detected by chest CT, as early as 1 month after RFA. However, according to our results, specificity of PET/CT at 1 month post-RFA is low showing values of only 58%. At an early stage, the relapsed lesion is often small in diameter and is embedded inside the ablation zone without visible changes in morphologic aspect and/or contrast
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ROC curves 1.0
True positive rate
0.8
0.6
0.4
0.2 ΔSUVmax (1 mo) ΔSUVmax (3 mo) RI (3 mo)
0.0 0.0
0.2
0.4
0.6
0.8
1.0
False positive rate Fig. 2. ROC curves analysis of PET/CT using the RI at 1 month and SUVmax at 1 month and 3 months after radiofrequency ablation.
enhancement. Moreover, the number of inflammatory uptakes on FDG PET is also high at early stages after RFA.21 Zhuang et al. observed in a study with mice that activity curves of 18 F-FDG in inflammatory lesions varied, with a rise in the first hour followed by a progressive decline. In contrast, tumor lesions showed an upward activity curve right from the start, stabilizing at a maximum at 2 h post-injection.18 Lin et al. do not support the routine use of dual time-point imaging with FDG PET in the differential diagnosis of pulmonary nodules.22 However, they suggest that PET may provide additional information in specific cases with equivocal results from initial scanning. Contrast-enhanced CT demonstrated the lowest accuracy levels and they concluded that dual time-point PET imaging was the most sensitive, whereas initial PET imaging was the most specific. In our series, changes in SUVmax between standard and delayed images using the RI at 1 month postRFA showed a sensitivity and PPV of 83%, with high specificity and NPV of 92%. These results suggest that PET/CT is able to provide an earlier detection of cases where RFA treatment has not been successful, allowing prompt retreatment of the lesions. Despite the small number of cases in this study, results would indicate that dual time point may be useful in monitoring these patients. The RI has been used in the diagnostic of liver or lung metastases by other authors using a threshold of 10%13,15,22–24 which is similar to the threshold obtained in this study using the ROC curves (17%). In a previous work of our group using PET/CT in operated colorectal cancer, the results showed that delayed images were able to significantly diagnose a higher number of liver metastases (66/79) compared to standard images (57/79).24 Nilendu et al. evaluated the role of FDG PET in assessing the response of lesions to RFA. Surveillance with FDG PET examinations performed serially can be used for early diagnosis of recurrence.25 It should be noted, however, that the use of FDG PET for the monitoring and surveillance of lung lesions is not yet well established, and exact time points for follow-up imaging are yet to be defined. Further work based on the promising findings from pilot studies will be needed to ensure the early detection of recurrence and progressive disease, which can give the patient an opportunity to be treated with alternative therapies. Focusing in the progression of the disease, two different situations may occur, the appearance of disease away from the treated lung metastasis after complete response to RFA or both distant disease and a progression of the
treated lesion. Actually, 5 out of the 6 cases of disease progression seen on follow-up also showed a local recurrence of the treated lung metastasis. In cases where disease progression was found after incomplete response of the treated lesion to RFA, an earlier detection of incomplete treatment would have probably improved survival in these patients who are no longer candidates for locally curative therapeutic options. In summary, monitoring of the RF-treated lesion is actually difficult, until at least 3 months after the ablative procedure, and a too long delay for retreatment of recurrence may be a loss of chance for the patient. Investigating whether FDG PET-CT dual time-point can show persistence of malignancy as early as possible is relevant. In addition, there is still limited data in the literature to establish the role of PET/CT in the follow-up of RFA of lung metastases. To our knowledge, this is the first study using dual time point at 1 month after RFA of lung metastases showing better results than standard variations on SUVmax at 3 months after treatment. These results indicate that using dual time point images at 1 month we could earlier detect the persistence of tumor due to incomplete RFA, or it could prevent the progression of the disease with more efficacy than the standard methods currently used. Conclusion In conclusion, dual time-point images with PET/CT at one month after RFA show better results than standard PET/CT in patients with solitary lung metastases from digestive cancer. The results indicate that the retention index obtained with dual time-point PET/CT at one month is more appropriate than SUVmax changes to detect persistent tumor in lung metastases treated with RFA, and, when this is the case, further procedures should be performed to rule out malignancy due to incomplete treatment. Conflict of interest The authors declare no conflicts of interest. Acknowledgement This work was supported by AGAUR 2014 SGR 279. References 1. Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, et al. The International Registry of Lung Metastases. Long-term results of lung metastasectomy prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg. 1997;113:37–49. 2. Yan TD, King J, Sjarif A, Glenn D, Steinke K, Morris DL. Percutaneous radiofrequency ablation of pulmonary metastases from colorectal carcinoma: prognostic determinants for survival. Ann Surg Oncol. 2006;13:1529–37. 3. Tampellini M, Ottone A, Bellini E, Alabiso I, Baratelli C, Bitossi R, et al. The role of lung metastasis resection in improving outcome of colorectal cancer patients: results from a large retrospective study. Oncologist. 2012;17:1430–8. 4. De Baère T, Palussière J, Aupérin A, Hakime A, Abdel-Rehim M, Kind M, et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: prospective evaluation. Radiology. 2006;240:587–96. 5. Gillams AR, Lees WR. Radiofrequency ablation of lung metastases: factors influencing success. Eur Radiol. 2008;18:672–7. 6. De Baère T. Lung tumor radiofrequency ablation: where do we stand. Cardiovasc Intervent Radiol. 2011;34:424–30. 7. Tominaga J, Miyachi H, Takase K, Matsuhashi T, Yamada T, Sato A, et al. Timerelated changes in computed tomographic appearance and pathologic findings after radiofrequency ablation of the rabbit lung: preliminary experimental study. J Vasc Interv Radiol. 2005;16:1719–26. 8. Anderson EM, Lees WR, Gillams AR. Early indicators of treatment success after percutaneous radiofrequency of pulmonary tumors. Cardiovasc Intervent Radiol. 2009;32:478–83. 9. Bojarski JD, Dupuy DE, Mayo-Smith WW. CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: results in 32 tumors. AJR Am J Roentgenol. 2005;185:466–71.
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