1. Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? Suresh Senan, Marinus A Paul, Frank J Lagerwaard Lancet Oncol 2013; 14: e270–74 R4 김승민 /prof 정재헌

2. Introduction The randomised controlled National Lung Screening Trial (NLST) reduction in lung-cancer-related mortality of 20% and in overall mortality of 6.7% when using low-dose CT In the NLST trial, screen positivity greatest nodule diameter of 4 mm or larger, 24% of all CT screens were positive using this definition. screened patients with benign lesions could have invasive diagnostic procedures such as a trans-thoracic needle biopsy or surgery, with a risk of complications. Approaches such as the nodule volume doubling time(VDT) and PET scans can minimise the risk of false-positive findings

3. Introduction if ¹ ⁸ F-FDG-PET uptake and VDT are in accordance, the probability of a false diagnosis of malignancy is small (5%) The diagnostic evaluation and treatment for patients enrolled in the NLST were mostly done at expert centres The potential for harm when CT screening in the community setting is significantly higher, as shown by higher complicationsrates of CT-guided biopsy of pulmonary nodules in population-based data. Similarly, surgical mortality and morbidity for lung cancer in population settings are inferior to those reported in clinical trials or specialised surgical databases

4. Introduction An anatomical surgical resection is the current standard of care for patients with early-stage NSCLC many patients do not have surgery because of age-related and tobacco- related comorbidity. stereotactic ablative radiotherapy (SABR) treatment of early-stage lung cancer in patients unfit for surgery. SABR is a high-precision radiotherapy technique for tumour ablation given in an outpatient setting, with few side-effects and high local control rates. Data from population-based studies reveal that use of SABR has led to better survival than conventionally fractionated

5. Introduction SABR has also been shown to achieve high cure rates in potentially operable patients. The growing evidence on SABR outcomes has led to discussions about optimum treatment of screen-detected tumours. The number of patients presenting for a resection has been estimated to potentially increase by ten times if CT screening becomes widespread, with significant potential for morbidity and even mortality. In this Review we address the pros and cons of both modalities in the treatment of screen-detected stage I NSCLC

6. Surgery as the preferred treatment for screen detected tumours imaging techniques provide only a likelihood of malignancy and never a certain diagnosis, even for large nodules. False-positive PET scans could arise in cases of focal pneumonia, aspergilloma, granulomas, inflammation, and tuberculosis. an exact diagnosis before treatment can only be established by tissue sampling, and this process is often attempted by CT guided fine-needle biopsy. Although the sensitivity and specifi city of such biopsies are higher than 80% in nodules larger than 1 cm, results are inferior for nodules measuring less than 8 mm, even in experienced hands.

7. Surgery as the preferred treatment for screen detected tumours a biopsy reported as non-diagnostic or uncertain benign is not uncommon in small nodules, 11% of patients so-classified were subsequently shown to have NSCLC on follow up. video-assisted thoracoscopic (VATS) wedge resection is the preferred next step when no definitive diagnosis is made A major advantage of a surgical resection malignancy is diagnosed on frozen section, an anatomical resection, with an adequate lymph node dissection during the same session. A lobectomy is still regarded as the standard of care a randomised trial that compared lobectomy with a sublobar resection in patients with a stage IA NSCLC showed local recurrence increased by three times with limited

8. sublobar resections as an alternative to lobectomy. Such a formal anatomical resection with lymph node dissection could lead to pathological upstaging of disease in up to 30% of patients. Subsequently, guideline specified adjuvant chemotherapy can be administered when occult nodal metastases are identified. Another reason to opt for an accurate tissue diagnosis is that 5-year disease-free survival in stage I disease ranges from 60–80% For treatment to advance, data for biological factors and markers that might determine the natural history of tumours and survival are needed. Surgery as the preferred treatment for screen detected tumours

9. A final argument in favour of surgery is the fact that local control could be difficult to evaluate after SABR because focal areas of fibrosis can arise that might continue to evolve for many years after treatment. Such changes need expert multidisciplinary review, and occasionally biopsies, to differentiate from tumour recurrence SABR-associated side-effects such as chest pain and rib fractures can develop after treatment of tumours close to the thoracic wall. More serious complications, such as bronchial stenosis, have been reported after SABR of centrally located tumours Surgery as the preferred treatment for screen detected tumours

10. Role of SABR in the treatment of stage I NSCLC SABR is now an established curative treatment for patients with a stage I NSCLC who are unfit for surgery, data for 4605 patients from the Netherlands Cancer Registry revealed an improvement in median survival of 9.3 months in patients aged 75 years & older who had radiotherapy between 2001 and 2009. Among patients who were fit to have surgery, but were instead treated with SABR, there were no deaths within 30 days of treatment, and local control rates were 98% at 1 year and 93% at 3 years. 3-year regional and distant failure rates were each 10%, and the median overall survival exceeded 5 years. A similar Japanese report in operable patients found a 3-year survival of 80% in T1N0 and 70% in patients with T2N0

11. Surgery or SABR: weighing the arguments In Dutch patients aged 75 years or older, a population-based study 30- day and 90-day mortality rates after surgery for stage I NSCLC 5.4% and 9.3% A systematic review of treatment outcomes in patients with severe chronic obstructive pulmonary disease and stage I NSCLC reported no 30-day mortality after SABR, but the 30-day mortality ranged from 7% to 25% after surgery, By contrast with the reductions in quality of life observed after surgery, studies after SABR in mostly unfit patients showed no such decreases Specifically, survivors of stage I lung cancer are at increased risk of subsequent malignancies.

12. Surgery or SABR: weighing the arguments Postsurgical recurrences range from 6% to 10% per person-year in the first 4 years after surgery most new primary cancers (93%) are identified by a scheduled CT scan of the thorax. These findings support use of CT scans every 6 months for the first 4 years after therapy. When a definite diagnosis of malignancy is difficult to make in screen- detected sub-centimetre lesions, a decision to proceed to treatment is justified only if the risks of a cancer are sufficiently high. The probability of malignancy can be calculated for individual patients using models based on clinical, radiological, and ¹ ⁸ F-FDG-PET features.

13. Surgery or SABR: weighing the arguments Guidelines of the American College of Chest Physicians recommend a surgical resection when the likelihood of a malignancy exceeds 60%. In the Netherlands, identification of malignancy using the combination of CT findings and a positive PET scan results in a final pathological diagnosis of benign disease in less than 4% of patients. Similar clinical outcomes have been reported after SABR for patients either with or without pathological findings, and the calculated probability of malignancy in both groups was nearly 95%. These studies involved treatment of lesions that were predominantly 1 cm or larger, and not subcentimetre lesions typically found on CT screening.

14. Surgery or SABR: weighing the arguments selection of patients for SABR when no pathological diagnosis is available, by combining VDT with a predictive model to establish a high risk of malignancy (>85%), is reasonable. SABR is particularly advantageous in patients who meet criteria that make them high-risk for surgical complications. Studies that explored use of serum proteomic signatures or the detection of upregulated genes in endobronchial epithelial-lining fluids could offer promise in this setting to minimise the risk of treating benign diseases. The ability to accurately stage nodal disease has been deemed an advantage of surgery because surgery will show that up to 20% of patients with a clinical stage I NSCLC have occult nodal metastases.

15. Surgery or SABR: weighing the arguments However, screen-detected lung tumours are reported to have a lower incidence of unexpected nodal metastases than non-screen-detected tumours. Patients with nodal metastases have a modest survival benefit with adjuvant chemotherapy. Surprisingly, regional nodal failures after SABR for lesions with a median diameter of 3 cm are seen in only 13% of cases, and the lower-than- expected nodal recurrence rates after SABR could be attributable to immunological responses. Furthermore, in surgical patients regional lymph node recurrences are not infrequent even after a complete nodal staging to confirm the absence of disease.

16. Surgery or SABR: role of the patient in decision making Patients increasingly wish to participate in making decisions that take into account their personal preferences, patients receive detailed information about risks of detection of abnormalities, the probability of additional invasive procedures, and risk of a final benign diagnosis. Surgery and SABR are two curative treatments that differ significantly in the risks of morbidity and mortality. Therefore, development of patient decision aids that provide accurate information about options and the uncertainties, benefits, and harms of treatment

17. Conclusions For peripheral screen-detected early-stage lung cancer detected in fit patients, a guideline-specified surgical resection seems to be the preferred treatment because it provides a definitive diagnosis and accurate staging. Such patients could benefit from tailored therapy if occult nodal metastases or adverse prognostic factors are found at histological examination. Patients who are at high risk of surgical complications should be informed of the merits of SABR, since surgery could be overtreatment, especially if the lesion is ultimately found to be benign.

18. Conclusions Between these two categories are many patients for whom the best approach is still open for debate, and they should ideally participate in a randomised trial comparing surgical resection with SABR. However, all patients should also be informed about the available clinical results of SABR, and decision aids should be developed to assist those who wish to participate in decision making (panel). Validated predictive models should be used in this setting to minimise the risk of treatment of benign lesions. Careful evaluation by a team of thoracic surgeons, nradiation oncologists, interventional radiologists, and medical oncologists should guide decision making in each patient with NSCLC.