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Clinical Question

Among patients with metastatic lung tumors who are not candidates for surgical resection, is cryoablation safe and does it offer effective local tumor control?

Bottom Line

Cryoablation therapy among patients with metastatic lung tumors was found to be safe and effective with a persevered quality of life following treatment.

Major Points

Among patients with oligometastatic lung disease surgical resection is the standard of care. However, for many patients’ surgery is not an option because of age, comorbidities, respiratory function, prior resection, or patient refusal. For these patients, less invasive image guided ablation and radiation therapy is increasingly offered and include radiofrequency ablation, microwave ablation and cryoablation. Of these, cryoablation offers a unique advantage in that it allows visibility of the ablation margin which defines the ablation zone for complete tumor ablation while avoiding adjacent normal tissue. Additionally, it can be used along the pleura without procedural pain. Due to the limited data on cryoablation for treatment of pulmonary metastases, this study set out to determine the feasibility, safety, and local tumor control of cryoablation for lung metastasis. This international multicenter prospective study enrolled 40 patients who qualified for the trial and underwent cryoablation for a total of 60 metastases. Patient specific follow up was done within the first week and at 1,3,6 and 12 months after the procedure. Technical success was defined by at least 5-mm circumferential ablative margin at the end of cryoablation. Local tumor control assessment was based on imaging done at 6 and 12 months using the ablation zone at 3 months as a comparative baseline. Assessment of tumor progression or incomplete ablation was based on changes relative to the 3-month baseline. Tumor response was calculated using the diameter of the ablation zone and was compared with a 3-month baseline. Complete response was defined as reduction of 75%, and partial response as 30% to 75% decrease. Stable disease was defined as less than 30% decrease and less than 20% increase in size. Local failure was defined as greater that 20% increase compared with the smallest ablation zone or the appearance of nodular enhancement. Thirty five of the 40 patients were included in the 12 month follow up. The primary efficacy outcome for overall local tumor control after ablation at 12 months for the combined stable, partial, and complete response was seen in 91.4% of patients and 94.2% of metastases. Local failure was observed in 5.8% of metastases at 6 and 12 months. There was no significant difference in the rate of tumor progression or incomplete ablation as a function of original treated tumor diameter (p=0.04). At 12 months 40% of the 35 patients developed additional metastatic disease with a mean time to new metastases disease post cryoablation of 10.7 months (SD ± 3.6). The SF-12 quality of life questionnaire revealed no clinically meaningful adverse impact on quality of life after cryoablation. One year disease specific survival and overall survival rates were 100% and 97.5%, respectively. Although surgical resection remains the standard procedure for lung metastases, many patients are not surgical candidates. This trial was the first prospective, multicenter study of image guided percutaneous cryoablation for the treatment of lung metastases. The results compared favorably with the reported results utilizing other focal therapies including SBRT, RFA and microwave ablation. Cryoablation offers additional advantages compared to RFA and microwave ablation including, less procedural pain, easy monitoring of the ablation zone during the procedure and early identification of treatment failure. However, this study only included a small number of patients with a relatively short follow up assessment of local tumor control. Additionally, follow up assessment on local tumor control utilized a 3-month post cryoablation image for baseline comparison and not a pretreatment image. Lastly, patients enrolled in this trial have mixed primary histology and cancer specific survival cannot be compared with sufficient statistical power.

Guidelines No Guidelines

Design

Multicenter, international, prospective, single arm N= 40 Setting: 4 centers (One in Europe, and three in united states) Enrollment: 2012-2013 Duration of follow up: 12 months. Analysis: Intention-to-treat

Primary outcome: To assess the feasibility, safety, and local tumor control of cryoablation for treatment of pulmonary metastases.

Population

Inclusion Criteria 18 years old or more Pulmonary metastatic disease Eastern cooperation oncology group score of 0-2 Karnofsky performance scale score greater than or equal to 60 Maximum of three metastases unilaterally or a total of five bilaterally Size of largest metastasis 3.5 cm or smaller No previous targeted local therapy to the currently targeted lung metastasis

Exclusion Criteria Platelet count less than 50,000/mm3 International Normalized Ratio greater than 1.5 Evidence of infection or neutropenia Baseline Characteristics Average age 62.6 years old with SD±13.3 Gender 24 (60%) Male 16 (40%) Female BMI 26.7 SD± 5.3 Primary tumor histology Colorectal 17 (42.5%) Renal cell carcinoma 7 (17.5%) Sarcoma 4 (10%) Other 12 (30%) Previous focal treatments for other lung metastases Radiation surgery 5 (13%) Surgery 14 (35%) Cryoablation 3 (8%) RFA 7 (18%) Microwave 2 (5%) Tumor characteristics Mean tumor diameter (cm) 1.4 ±0.7 (range 0.3-3.4) Tumor size (cm) 0.3-1.0 18 (30%) 1.1-2.0 30 (50%) 2.1-3.0 11 (18.3) ≥3.1 1 (1.7%) Number of tumors treated per patient 1.8±1.0(range 1.0-4.0) Tumor distribution Unilateral 32 (80%) Bilateral 8 (20%)

Interventions

Cryoablation needles were placed under CT-scan guidance strategically to cover the tumor with an adequate margin of lethal ice. The cryoablation procedure was then performed in a three-cycle freeze-thaw phase protocol. Non-contrast CT imaging was used during and after each procedure to monitor the evolving ablation zone.

Outcomes

Primary Outcome Local tumor control rate was 96.6% and 94.2% at 6 and 12 months, respectively. Percutaneous cryoablation was well tolerated with CTCAE grade 3 occurring in 6% of patients Adverse Events Pneumothorax requiring chest tube: 18.8% CTCAE grade 3 adverse events within 30 days: 6% Pneumothorax requiring pleurodesis Thrombosis of hemodialysis access arteriovenous fistula requiring thrombectomy Noncardiac chest pain

Criticisms This study included a relatively small number of patients and a relatively short follow up for assessment of local tumor control. Patients included in this trial had mixed primary tumor histology and cancer specific survival cannot be compared with sufficient statistical power. Follow up imaging utilized the structure and size of the ablation zone at 3 months as a baseline comparison and not pretreatment tumor size as standard in RECIST and other oncologic evaluations.

Funding

This study was supported by Galil Medical.

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