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A. Wozniak

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    PC 01 - Pro vs Con: Surgery vs. SBRT in Operable NSCLC / Pro vs Con: SBRT for Non-Biopsied Lung Nodules (ID 47)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 4
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      PC01.01 - Surgery vs. SBRT in Operable NSCLC - SBRT (ID 2026)

      14:15 - 15:45  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Stereotactic ablative radiotherapy (SBRT, or SABR) is the guideline-recommended treatment for a peripheral stage I non-small cell lung cancer in patients who are unfit for surgery, or those who decline surgery. In patients fit to undergo surgery, no phase three randomized trial comparing the two modalities has been completed to date. However, comparative effectiveness research suggests that a similar disease-free survival and loco-regional control can be achieved with the two modalities [Louie AV 2015a]. At present, the only available prospective randomized data available in operable NSCLC reveals a 3 year rate of freedom from local recurrence of 96% (95% CI 89–100) in patients treated using SBRT, compared with 100% (95% CI 100–100) for patients in the surgery group (log-rank p=0.44) [Chang J, 2015]. With a number of new randomized clinical trials now in preparation, it is useful to understand the main reasons for a reluctance to believe that 2 treatment modalities are comparable. The poorer overall survival reported in the SBRT literature led to the suggestion that early deaths may be due to poor disease control and/or unrecognized toxicity. However, patients treated in early studies of SBRT often had multiple comorbidities, a factor which also decreases survival in surgical patients. For example, data from the Danish Cancer registry on resected patients reported a 5-year overall survival of 38% (95% confidence interval 23-53%) for pT1 and Charlson comorbidity score 3+, versus a 5-year overall survival of 69% (CI 62-75%) for pT1 and no comorbidity [Luchtenborg M, 2012]. An externally validated prognostic validation tool consisting of a recursive partitioning analysis (RPA) and nomogram, the Amsterdam prognostic model (APM), has been developed for overall survival after SBRT [Louie AV, 2015b]. While the nomogram retained strong performance across surgical and SBRT external validation datasets, RPA performance was poor in surgical patients, suggesting again that two distinct patient populations are now being treated with these local modalities. It has been argued that the identification of nodal metastases during surgery, followed by adjuvant chemotherapy, can lead to superior survival with surgery, as occult nodal metastases may be missed in patients who undergo SBRT after PET-CT staging. However, even recent surgical publications indicate that guideline-specified nodal staging is not being performed in a significant number of patients, but that this difference was not detrimental. Danish Cancer Registry data revealed that nodal upstaging for clinical stage I NSCLC was lower after VATS than after open lobectomy, but also that that the extent of nodal harvest did not influence overall survival [Licht PB, 2013]. The IELCAP investigators reported on outcomes in 347 patients, where of the patients undergoing sub-lobar resection and lobectomy, more than 40% and approximately one quarter, respectively, did not even have a single mediastinal lymph node biopsied [Altorki NK, 2014]. We previously argued that the benefits of surgical nodal harvest are modest at best in this patient population. The lack of clear benefit for a nodal dissection, particularly in patient groups with a stage I NSCLC at increased risk of postoperative complications will limit the benefits of primary surgery. This is not a totally unexpected finding as recent studies have shown that more extensive nodal surgery was not beneficial in malignancies of the breast, esophagus and stage III melanomas with micrometastasis to the sentinel nodes. Cost-effectiveness analyses have consistently demonstrated that SBRT is cost-effective when compared to sublobar resection [reviewed in Louie AV, 2015]. Survivors of both surgery and SBRT are at risk of a second primary lung cancer, at a rate varying from 3-6% per person year [Lou F, 2013; Verstegen N, in press]. Lung cancer deaths predominate in the first 5 years after treatment, after which the relative contribution of cardiovascular and COPD causes of death increases [Janssen-Heijnen M, 2015]. It has been argued previously that “to expose patients to a hypofractionated SABR without mature evidence of absence of its toxicity would be hazardous” [van Schil P, 2013]. As long-term follow-up data after SABR is now available [Verstegen N, 2015], and as SABR has clearly fewer post-treatment complications than a surgical resection [Chang J, 2015], it is only appropriate to discuss all these findings with patients in the context of shared decision-making. Much of the recent debate has focused on pathological staging and techniques. However, there is growing awareness of the importance of ‘value in healthcare’. Both patients and their insurers increasingly wish to know what their life will be like after treatment, if they will return to work, and if their symptoms will improve [http://www.ichom.org/]. In the near future, patient reported outcome measures (PROMs) are likely to take a complimentary role in decisions about the choice of local therapy for stage I NSCLC, as high-quality data from randomized clinical trials are awaited. References Louie AV. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons. Radiotherapy and Oncology 2015 ;114:138-47. Chang JY. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16:630-7. Lüchtenborg M. The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients. Eur J Cancer. 2012 48:3386-95 Louie AV. Predicting Overall Survival following Stereotactic Ablative Radiotherapy in Early-Stage Lung Cancer: The Amsterdam Prognostic Model. Int J Rad Oncol Biol Phys in press. Licht PB. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg. 2013;96:943-9; Altorki NK. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. J Thorac Cardiovasc Surg. 2014 Feb;147:754-62; Lou F. Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013 ;145:75-81 Verstegen NE. Patterns of disease recurrence after SABR for early stage non-small cell lung cancer: Optimizing follow-up schedules for salvage therapy. J Thorac Oncol in press Janssen-Heijnen ML. Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis. Ann Oncol. 2015;26:902-7 van Schil PE. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. Lancet Oncol. 2013;14(10):e390.

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      PC01.02 - Surgery vs. SBRT in Operable NSCLC - Surgery (ID 2027)

      14:15 - 15:45  |  Author(s): P. Van Schil

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Surgery vs. SBRT in operable NSCLC Surgery Over the last years stereotactic radiotherapy (SRT) has emerged as an alternative treatment to surgical resection for treatment of localized, early-stage non-small cell lung cancer (NSCLC). Precise delivery of high-dose radiotherapy has become possible to eradicate the primary tumor (1). SRT has mainly been applied for functionally inoperable patients with severe cardiopulmonary morbidity. Recently, the question has emerged whether SRT is also a valid oncological treatment in technically and functionally operable patients. At the present time, no randomized studies are available directly comparing SRT and surgical resection with systematic lymph node dissection. Several trials were initiated but they were closed prematurely due to poor accrual. SRT is certainly emerging as a valid therapeutic option. However, from a thoracic surgical point of view several concerns remain when applying SRT to operable early-stage NSCLC: precise pathology is not obtained in all cases, no precise information is available on locoregional lymph node involvement making it difficult to recommend adjuvant chemotherapy in specific cases, and in general, different criteria are applied when comparing results of surgery and SRT. This applies specifically to the definition of local recurrence which gives rise to a potential comparison bias and limits the accuracy of long-term evaluation (2, 3). Moreover, thoracic surgeons are more and more confronted with “salvage surgery” after previous radiotherapy when no other therapeutic options are available (4). Technically, these resections can be very challenging. As no high-grade evidence is available, different opinions prevail in present-day literature. In a pooled analysis of two randomised trials comparing SRT with lobectomy for stage I NSCLC that closed prematurely due to poor accrual, the authors concluded that SRT could be an option for treating operable stage I NSCLC. However, as the authors indicate themselves, because of small patient sample size and short follow-up time, further randomized studies should be performed before more definite recommendations can be made (5). In contrast, in a recent propensity score analysis 41 patients who underwent video-assisted (VATS) lobectomy were matched with 41 patients treated with SRT for stage I NSCLC (6). Significant differences were found in overall survival, cause-specific survival, recurrence-free survival, local and distant control favoring VATS lobectomy. Conclusion of this study was that VATS lobectomy may offer a significantly better long-term outcome than SRT in potentially operable patients with biopsy-proven clinical stage I NSCLC. In another propensity score analysis long-term survival was compared between SRT and sublobar resection for stage I NSCLC in patients at high risk for lobectomy (7). In 53 matched pairs the difference in overall survival was not significant and the cumulative incidence of cause-specific death was comparable between both groups. Conclusion of this study was that SRT can be an alternative treatment option to sublobar resection for patients who cannot tolerate lobectomy because of medical comorbidities. In June 2015 the “Comité de l’Evolution des Pratiques en Oncologie (CEPO) from Québec, Canada published its recommendations regarding the use of SRT (8). For medically operable patients with T1-2N0M0 NSCLC surgery remains the standard treatment due to the lack of scientifically valid comparative data. For medically inoperable patients with T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SRT should be preferred to external beam radiotherapy, a biological equivalent dose (BED) of at least 100 Gy should be administered, and the choice of using SRT should be discussed within a tumor board. Radiotherapy should not be considered for patients whose life expectancy is very limited because of comorbidities. In conclusion, surgical resection remains the treatment of choice for patients with early-stage NSCLC who are functionally operable. After discussion within a multidisciplinary tumor board SRT may be considered for functionally compromised patients who cannot tolerate lobectomy. Further evidence is needed requiring cooperation between radiation oncologists and thoracic surgeons when designing comparative trials with strict inclusion criteria and precise definitions of endpoints. In this way a scientifically valid comparison between SRT and surgical treatment is provided. References 1. Louie AV, Palma DA, Dahele M, Rodrigues GB, Senan S. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2015;114(2):138-47. Epub 2014/12/17. 2. Van Schil PE, Van Meerbeeck J. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. The Lancet Oncology. 2013;14(10):e390. Epub 2013/09/03. 3. Van Schil PE. Results of surgery for lung cancer compared with radiotherapy: do we speak the same language. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2013;8(2):129-30. Epub 2013/01/19. 4. Van Schil PE. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010;5(12):1881-2. Epub 2010/11/26. 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. The Lancet Oncology. 2015;16(6):630-7. Epub 2015/05/20. 6. Hamaji M, Chen F, Matsuo Y, Kawaguchi A, Morita S, Ueki N, et al. Video-assisted thoracoscopic lobectomy versus stereotactic radiotherapy for stage I lung cancer. The Annals of thoracic surgery. 2015;99(4):1122-9. Epub 2015/02/11. 7. Matsuo Y, Chen F, Hamaji M, Kawaguchi A, Ueki N, Nagata Y, et al. Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: A propensity score matching analysis. Eur J Cancer. 2014;50(17):2932-8. Epub 2014/10/05. 8. Boily G, Filion E, Rakovich G, Kopek N, Tremblay L, Samson B, et al. Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non-Small-Cell Lung Cancer: CEPO Review and Recommendations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(6):872-82. Epub 2015/05/23.

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      PC01.03 - SBRT for Non-Biopsied Lung Nodules - Pro (ID 2028)

      14:15 - 15:45  |  Author(s): K. Rosenzweig

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has been rapidly adapted as a standard treatment for inoperable early stage non-small cell lung cancer (NSCLC).[1] Due to the potential risks of biopsy and the ability to evaluate and characterize pulmonary nodules on CT and [18]FDG-PET, centers have had differing standards of whether to treat patients without a pathologic diagnosis. In other diseases, there are well established protocols for treating without a pathologic diagnosis. For example, ten years ago, a diagnostic algorithm was developed and subsequently validated for the diagnosis of hepatocellular carcinoma based on imaging.[ 2] If a screened patient has a liver lesion is greater than 2 cm, shows arterial hypervascularity and venous washout, it is considered diagnostic. Two of the main techniques for establishing pathologic diagnosis for lung tumors are bronchoscopy and transthoracic needle biopsy (TTNB). Since solitary pulmonary nodules are frequently in the periphery, TTNB is the more frequently used method of diagnosis. Pneumothorax is a common complication of TTNB with rates varying in the literature from 9 – 54% with an average of around 20%.[3] Approximately 5% of patients undergoing TTNB require chest tube placement. In surgical series, the observed rate of surgical resection of non-malignant nodules ranges from 9 to 40%. Even programs with prospective CT-screening cohorts and nodule management protocols such as the International Early Lung Cancer Action Program report benign disease in 11% of resected patients.[ 4] Centers that have a relatively high proportion of treated patients with only a clinical diagnosis typically use criteria such as a new or growing lesion that is avid on [18]FDG-PET. Additionally, the probability of malignancy of a specific pulmonary nodule can be estimated based on statistical work of Swensen, et al. and Herder, et al. [5,6 ]The are numerous on-line calculators that incorporate these equations for evaluation of an individual patient. The VU University Medical Center in Amsterdam analyzed their results in patients who underwent SABR on whether they had a pathologic diagnosis.[ 7] In their prospective database of 591 patients, 35% had a pathologic diagnosis (biopsy proven) and 65% were diagnosed clinically. In a comparison of the two groups, the patients with a pathologic diagnosis had significantly larger tumor diameters and higher predicted FEV1 values. There was no significant difference seen in overall survival, local control regional or distant recurrences. In a retrospective analysis of 94 lesions (86 patients) treated with SBRT at the Cleveland Clinic, 35% of patients did not have tissue diagnosis.[ 8] They reported no difference in overall survival between these patients and those with pathologic confirmation. A prospective Phase II trial of SBRT from the Nordic Cancer Union was reported by Baumann, et al.[ 9] Nineteen (33%) of the 57 patients on the trial did not have pathologic confirmation of malignancy and only 14 of those 19 had [18]FDG-PET to help establish the diagnosis. Similar to the VU experience, patients with a pathologic diagnosis tended to have larger tumors. They reported no difference in progression-free, overall or cancer-specific survival between the subgroup with pathological confirmation and the whole patient group. The toxicity of lung SBRT is well established. In the VU experience reported above, they report Grade 3 or worse radiation pneumonitis in 3% of patients. Other complications include rib fracture and chest wall pain. As expected, there is no difference in toxicity between patients with or without pathologic diagnosis. There clearly is a role for SBRT in patients with radiographic-only confirmation of early stage NSCLC. In the centers where treatment of these patients is common practice, there is no evidence of differences in outcomes, nor excess toxicity. But the appropriate threshold for treatment of non-biopsied lung nodules is still unknown. Radiation oncologists need further input from our colleagues in diagnostic radiology, thoracic surgery and pulmonary medicine to develop specific guidelines on patients where biopsy could, and perhaps should, be avoided. This is especially true in countries where the potential of medical liability is relatively high since it is inevitable that some patients who actually do not have cancer will be treated with aggressive radiation therapy. References 1. Palma D, Senan S. Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer. Curr Opin Oncol 2011;23:133–9. 2. AASLD Guidelines; Hepatology 2011;53:1020-2 3.Boskovic, et al. Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance. J Thor Dis 2014; 6: S99-107 4. Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):1619-1626 5. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch of Int Med 1997;157:849–55 6. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18Ffluorodeoxyglucose positron emission tomography. Chest 2005;128:2490–6. 7. Verstgen, N., et al., Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease. Radiotherapy and Oncology 101 (2011) 250–254 8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol 2009;4:976–82. 9. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–6.

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      PC01.04 - SBRT for Non-Biopsied Lung Nodules - Con (ID 2029)

      14:15 - 15:45  |  Author(s): R.D. Timmerman

      • Abstract
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      Abstract not provided

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