2. Radiofrequency Ablation For Treatment Of Peripheral Non Operable Non Small Cell Lung Cancer Mohamed Khairy El-Badrawy**, Adel El- Badrawy*, Amany Zeidan**, Saleh El-Essawy*, Omaima Badr**, Mohamed Awad*** Radiology*, Thoracic Medicine**, Oncology*** Departments Mansoura Faculty of Medicine Egypt

3. Lung cancer is the leading cause of cancer-related mortality in both men and women in the US. It causes more death than colorectal cancer, breast cancer, and prostate cancer combined. Non-small-cell lung cancer (NSCLC) constitutes about 80% of primary malignant tumors in the lung.

4. Although surgical resection remains the mainstay of therapy for early stage non– small cell lung cancer (NSCLC), most patients present with advanced disease. In addition, many patients with respectable early stage disease are unfit for surgical lung resection.

5. Tumor destruction with heating The capability of heat to kill cancerous cells has been known for several decades. Tumor cells are more sensitive to heat than normal tissue and temperatures as low as 41°C can destroy caner cells. (Dupuy et al., 2006).

6. Ablative therapies Many ablative therapies had been studied as minimally invasive alternatives to surgery in patients unfit for surgery or with advanced disease. –Anticipated reduced morbidity and mortality, –Low cost, –Suitability for real-time imaging guidance, –Can be done on an outpatient basis.

7. Advantages of RFA Radiofrequency ablation (RFA) has become the imaging-guided ablative method of choice because of: –its relatively low cost, –its capability of creating large regions of coagulative necrosis and –its relatively low toxicity (Abbas et al., 2007).

8. Heat-based ablative methods Heat-based ablative methods such as: –Radio-frequency (RF) ablation, –Microwave ablation, –Laser ablation (Dupuy et al., 2000).

9. Technique of RFA RFA involves the application of high-frequency alternating current to heat and coagulate target lesions. RFA systems have three components –A generator –An active electrode that is placed within the tumor –A dispersive electrode (bovie pad) placed on the thighs of the patient. Schaefer et al., 2003):

10. Theory of RFA As the radiofrequency energy moves from the active electrode to the dispersive electrode and then back to the active electrode, ions within the tissue oscillate, resulting in frictional heating of the tissue. As the temperature within the tissue rises to greater than 60 ○C, instantaneous cell death occurs because of protein denaturation and coagulation necrosis (Fernando et al., 2005).

11. Guidance in RFA Advances in CT and US technology allows accurate localization of an electrode. Refinement of the electrode was necessary to deliver a well-defined area of thermal energy to larger volumes of tumor tissue.

12. RFA in lung cancer Patients not candidates for surgery owing to poor cardio-respiratory reserve, RF ablation alone or followed by conventional radiation therapy with or without chemotherapy may prove to be a treatment option (Dupuy and Goldberg., 2001).

13. RFA in metastasis Ablation of a small tumor Size reduction of larger tumors. Palliation of chest wall or osseous metastatic tumors (Hiraki et al., 2006).

15. Components of RFA system; active electrode in tumor, dispersive electrodes (bovie pads), and generator.

16. FDA approval of RFA There are three FDA–approved devices available for the performance of RFA (Steinke et al., 2004):  Boston Scientific (Boston, MA),  RITA (Mountainview, CA),  Valley Laboratory (Boulder City, CO).

17. RFA electrodes The electrode is available in varied lengths and has an insulated shaft and an uninsulated active tip that emits the RF current. 1.Tumors larger than 4 cm are treated with a cluster RF electrode that consists of three 17-gauge RF electrodes spaced 5 mm apart. 2.Tumors smaller than 4 cm are treated with a single RF electrode. 3.Tumors smaller than 2 cm are treated with a 1-cm-long active tip, 4.Those between 2 and 3 cm are treated with a 2-cm-long active tip, 5.Those between 3 and 4 cm are treated with a 3-cm-long active tip. The RF electrode is positioned with the electrode shaft parallel to the longitudinal axis of the tumor. The tip of the RF electrode is positioned against the deepest margin of the tumor for the first treatment. Axial and craniocaudal placement of the RF electrode is confirmed with CT fluoroscopy (5-mm collimation, 10 mA) (Zagoria et al., 2001).

18. Operative technique 1.Sedation and anaesthesia: Conscious sedation (achieved with intravenous administration of midazolam and fentanyl General anesthetic may be required Local anesthesia is achieved with injection of a 1% lidocaine both intradermally and into deeper tissues 2.Patients are monitored for O2 sat, ECG, and BP. 3.CT is used to localize the tumor and determine the optimal approach. 4.Standard surgical preparation and draping are performed. (Putnam et al., 1999).

19. Contraindications of RFA The absolute contraindication to lung RFA 1.Uncontrollable coagulopathy 2.Madiastinal tumors 3.Tumors adjacent to large vessels, esophagus and trachea. Relative contraindications include: 1.Poor performance status 2.Inability to safely access the tumor (eg, bullous disease or central tumor location). 3.Cardiac devices such as pacemakers and defibrillators, (Sano et al., 2007)

20. Complications of RFA 1.Pleurisy and small pleural effusions. 2.Cough. 3.Pneumothorax. 4.Acute pulmonary hemorrhage. 5.Bronchopleural fistula. 6.Systemic embolization, with potential stroke 7.Skin burns 8.Tumor seeding at the RFA track (Dupuy et al., 2002)

21. This study was done at Mansoura university Egypt over 3 years from 2008 to 2011. It was planned to evaluate the safety and efficacy of radiofrequency ablation in palliative treatment of peripheral non small cell lung cancer.

22. The patients were divided into 2 groups: Group A; included 10 patients who were subjected to one session of radiofrequency ablation followed by systemic chemotherapy. Group B; included 15 patients who were subjected to systemic chemotherapy alone.

23. All patients were subjected to the following:  Medical history: age, sex, occupation, residence, and smoking  Symptoms scoring: for cough, haemoptysis and chest pain (before, 3 and 6 months after the start of treatment.  Performance status: was done using Karnofsky performance scale.  General examination: of the patient and local examination of the chest.  Routine laboratory tests: Complete blood picture (CBC), liver functions tests, kidney function tests, coagulation profile and ABGs.

24.  Radiological investigations: X-ray chest. CT chest : The first and second CT for diagnosis and treatment planning, third was done immediately after RFA to assess the efficacy of the procedure and to detect the early complications, fourth, fifth and sixth CT` at 1, 3 and 6 months to evaluate the radiological changes in the tumour, size and delayed complications. Pelvi-abdominal ultrasonography, CT of the abdomen, CT brain and bone scan for exclusion of distant metastasis).

25.  Fiberoptic bronchoscopy.  Pulmonary function tests.  TNM staging.

26. Radiofrequency Ablation: was performed percutaneously under computed tomography fluoroscopic guidance with an array-type electrode (LeVee electrode) and radiofrequency generator (RF 3000 Boston Scientific Natick, Massachusetts, USA).

28. Demographic data and smoking index of the studied patients. Total ( N =25) Group B (N =15) Group A (N = 10) %n%n% n Sex 88%2286.7%1390%9Male 12%313.3%210%1Female Smoking 20%5 3 2Non smoker 4%16.7%100Mild 36%933.3%540%4Moderate 24%620%330%3Sever 16%420%310%1Ex-smoker

29. Tumor site of the studied patients. Total ( N =25) Group B (N =15) Group A (N = 10) %n%n% n Tumor site 40%1026.7%460%6Left side 12%36.7%120%2lower lobe 28%720%340%4upper lobe 60%1573.3%1140%4Right side 16%420%310%1upper lobe 28%733.3%520%2lower lobe 16%420%310%1middle lobe

30. Pathologic types of the tumors and age of the studied patients. Total ( N =25) Group B (N =15) Group A (N = 10) %n%n% n Pathology 32%826.7%440%4 Sq c c. 56%1460%950%5 Adeno c 12%313.3%210%1 Large c c P valueMean ± SD 0.3807.47 ± 1.31086.96± 1.5554 Tumor size 0.60756.5 ± 9.164158.4 ± 8.1268Age

31. Symptoms scoring and Karnofsky scale of the studied patients before the start of treatment. Karnofsky scale Haemoptysis CoughChest pain Mean ± SD 56.0 ± 13.49890.5 ± 0.7071 1.9 ± 0.3162 2.1 ± 0.4830Group A 52 ±8.61890.5 ± 0.5270 1.7 ± 0.4830 1.7± 0.279Group B 0.3730.8930.3280.18P value

32. Comparison between cough score before, 3 and 6 months after treatment in both groups. P value After 6 months After 3 months Before 0 vs 6 m0 vs 3 mMean ± SD < 0.001 0.2 ± 0.4216 0.3 ± 0.483 1.9 ± 0.316 Group A 0.003 0.8 ± 0.8338 0.9 ± 0.798 1.7 ± 0.483 Group B 0.0290.0350.328P value

33. Comparison between chest pain score before, 3 and 6 months after treatment in both groups. P value After 6 months After 3 months Before 0 vs 6 m0 vs 3 mMean ± SD < 0.001 0.1 ± 0.6320.2 ± 0.316 2.1 ± 0.483 Group A 0.0680.0921.2 ± 0.8841.2 ± 0.961 1.7 ± 0.279 Group B 0.003 < 0.0010.18P value

34. Comparison between haemoptysis score before, 3 and 6 months after treatment in both groups. P value After 6 months After 3 months Before 0 vs 6 m0 vs 3 mMean ± SD 0.104 0.1 ± 0.316 0.5 ± 0.707 Group A 0.6700.5820.6 ± 0.5070.4 ± 0.516 0.5 ± 0.527 Group B 0.011 0.0570.893P value

35. Comparison between Karnofsky scale before, 3 and 6 months after treatment in both groups. P value After 6 months After 3 months Before 0 vs 6 m0 vs 3 mMean ± SD ≤ 0.0010.01574 ± 9.661 66 ± 15.776 56.0 ± 13.499 Group A 0.2380.00655 ± 9.90457 ± 7.03752 ± 8.619Group B ≤ 0.0010.0730.373P value

36. Symptom improvement 6 months after treatment in both groups

37. Tumor sizes before and 6 months after treatment in both groups, measured with CT chest. P value After 6 months After 3 months Before 0 vs 6 m0 vs 3 mMean ± SD 0.0100.0065.29 ± 2.7785.774 ± 2.2266.96 ± 1.555 Group A 0.7870.6377.3 ± 2.0837.323 ± 1.6097.47 ± 1.311 Group B 0.0260.0490.380 P value

38. Radiological response in tumor mass after 3 months of treatment in both groups. ProgressionStable Total response PartialComplete %n%n%n%n%n 10%150%540%4 400 Group A (N = 10) 40%653.3%86.7%1 100 Group B (N = 15)

39. Radiological response in the tumor mass after 6 months of treatment in both groups. ProgressionStable Total response PartialComplete %n%n%n%n%n 20%240%4 430%310%1 Group A (N = 10) 60%926.6%413.3%2 200 Group B (N = 15)

40. Relation between the size of the tumors and the total response to treatment among the studied groups. Largest diameter > 5 cmLargest diameter ≤ 5 cm No responseResponseNo response Response %n%n%n%n 71.4%5/728.6%2/733.4%1/366.6%2/3 Group A 92.3%12/137.7%1/13100%2/20%0/2 Group B

41. Complications of radiofrequency ablation in group A. PneumothoraxHaemoptysisChest painFever %n%n%n%n 10%120%2 50%5 70% 7 Group A (N = 10)

42. Mean survival in both groups. P value survival (months) One year survival Mean ± SD 0.007 17.67 ± 2.1366% Group A 12.83 ± 2.7154% Group B

50. Conclusion 1.RFA is an adjuvant, effective and safe modality with minimal side effects as a palliative treatment for patients with inoperable peripherally located NSCLC. 2.Efficacy of RFA is better for smaller compared to larger tumors.

51. Conclusion 3.CT chest is a reliable method for assessing the precise therapeutic efficacy of RFA during follow up. 4.Combination of RFA and chemotherapy may improve the survival rate and quality of life.

52. Recommendations 1.Response may be better if the tumor is treated with multiple sessions of RFA. 2.To avoid the expected radiological hazards for the patients after repeated CT scans; other alternative more safe image modalities as ultrasound or MRI may be investigated for tumor localization, electrode insertion into the lung and follow up after RFA.

53. Recommendations 3. RFA may be used through FOB with use of long probes for palliation of endobronchial tumors. 4. RFA may be used for treatment of other intrathoraxic malignancies as pulmonary metastasis and mesothelioma as well as destruction of TB granuloma or mycetoma which are difficult and expensive to treat.