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D. Harpole
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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
- Moderators:D. Harpole, P. Yang, P. Bonomi, A. Wozniak
- Coordinates: 9/07/2015, 14:15 - 15:45, 601+603
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PC01.01 - Surgery vs. SBRT in Operable NSCLC - SBRT (ID 2026)
14:20 - 14:40 | Author(s): S. Senan
- Abstract
- Presentation
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)
14:40 - 15:00 | Author(s): P. Van Schil
- Abstract
- Presentation
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)
15:00 - 15:20 | Author(s): K. Rosenzweig
- Abstract
- Presentation
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)
15:20 - 15:40 | Author(s): R.D. Timmerman
- Abstract
- Presentation
Abstract not provided
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Author of
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GR 01 - Management of Challenging Clinical Scenarios in Localized Lung Cancer (ID 14)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:G. Darling, J. Mitchell
- Coordinates: 9/08/2015, 14:15 - 15:45, 601+603
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GR01.01 - T4 NSCLC Involving the Great Vessels: Role for resection? (ID 1828)
14:20 - 14:40 | Author(s): D. Harpole
- Abstract
- Presentation
Abstract:
Usually NSCLC tumors that have invaded the central/mediastinal vascular structures are considered unresectable, and staged as T4 locally-advanced NSCLC and are treated with concurrent platinum-based chemotherapy and thoracic radiation with curative intent (60+Gy). However, subsets of good functional status patients with limited involvement (clinically node-negative; T4N0) have been selectively treated with surgical resection before or after additional therapy. This has been most commonly employed for tumor invasion at the base of one of the pulmonary veins with extension into the proximal left atrium or for right upper lobe tumors with segmental involvement of the superior vena cava. Smaller series exist for resection of lung tumors having primary extension into the cardiac chambers and aortic arch. There are no prospective trials, only manuscripts that detail decades-long retrospective single institution series. This presentation will review the literature and surgical approaches to NSCLC involving the great vessel with and without circulatory support. Surgical management of lung cancer invading the aorta or the superior vena cava. Misthos P, Papagiannakis G, Kokotsakis J, Lazopoulos G, Skouteli E, Lioulias A. Lung Cancer. 2007 May;56(2):223-7. Epub 2007 Jan 16. Extended resection of the left atrium, great vessels, or both for lung cancer. Tsuchiya R, Asamura H, Kondo H, Goya T, Naruke T. Ann Thorac Surg. 1994;57(4):960-5 Results of superior vena cava resection for lung cancer. Analysis of prognostic factors. Spaggiari L, Magdeleinat P, Kondo H, Thomas P, Leon ME, Rollet G, Regnard JF, Tsuchiya R, Pastorino U. Lung Cancer. 2004 Jun;44(3):339-46. 15 years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer. Shargall Y, de Perrot M, Keshavjee S, Darling G, Ginsberg R, Johnston M, Pierre A, Waddell TK. Lung Cancer. 2004:357-63 Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Spaggiari L, Leo F, Veronesi G, Solli P, Galetta D, Tatani B, Petrella F, Radice D. Ann Thorac Surg. 2007 Jan;83(1):223-9; discussion 229-30 Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes. Galvaing G, Tardy MM, Cassagnes L, Da Costa V, Chadeyras JB, Naamee A, Bailly P, Filaire E, Pereira B, Filaire M. Ann Thorac Surg. 2014 May;97(5):1708-13 Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Yildizeli B, Dartevelle PG, Fadel E, Mussot S, Chapelier A. Ann Thorac Surg. 2008 Oct;86(4):1065-75; Twelve-year experience with left atrial resection in the treatment of non-small cell lung cancer. Ratto GB, Costa R, Vassallo G, Alloisio A, Maineri P, Bruzzi P. Ann Thorac Surg. 2004 Jul;78(1):234-7. Review. Survival after extended resection for mediastinal advanced lung cancer: lessons learned on 167 consecutive cases. Spaggiari L, Tessitore A, Casiraghi M, Guarize J, Solli P, Borri A, Gasparri R Petrella F, Maisonneuve P, Galetta D. Ann Thorac Surg. 2013;95(5):1717-25 Superior vena caval resection in lung cancer. Lee DS, Flores RM. Thorac Surg Clin. 2014 Nov;24(4):441-7
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MINI 06 - Quality/Prognosis/Survival (ID 111)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:R. Meguid, J. Yoshida
- Coordinates: 9/07/2015, 16:45 - 18:15, 605+607
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MINI06.05 - Discussant for MINI06.01, MINI06.02, MINI06.03, MINI06.04 (ID 3398)
17:05 - 17:15 | Author(s): D. Harpole
- Abstract
- Presentation
Abstract not provided
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MINI 20 - Surgery (ID 137)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:G. Veronesi, R. Flores
- Coordinates: 9/08/2015, 16:45 - 18:15, 201+203
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MINI20.04 - Right-Sided vs Left-Sided Pneumonectomy after Induction Therapy for Non-Small Cell Lung Cancer (ID 3064)
17:00 - 17:05 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the impact of laterality on long-term survival using the National Cancer Data Base (NCDB).
Methods:
Perioperative and long-term outcomes of patients who underwent pneumonectomy following induction chemotherapy ± radiation from 2003-2011 in the NCDB were evaluated using Kaplan-Meier method, multivariable logistic regression analysis and multivariable Cox proportional hazards modeling.
Results:
During the study period, 1,652 patients met inclusion criteria, of whom 740 (45%) underwent right-sided pneumonectomies. Right-sided patients were more likely to have adenocarcinomas, cN2 disease and lower co-morbidity scores (Table). The 30-day mortality rate was higher for right-sided procedures in univariable (11% [84/740] vs 4% [39/912], p<0.001) and multivariable (OR 9.1 [1.8-50.0], p<0.01) analysis. However, 5-year overall survival between right and left pneumonectomy were not significantly different (figure) after a median follow up of 30.2 months. Right-sided procedure also did not impact overall survival in multivariable analysis (hazard ratio (HR), 1.41 [95% CI: 0.87-2.27], p=0.16), while increasing age (HR, 1.02 [95% CI: 1.01-1.03]), Charlson co-morbidity Score of 2 (HR, 1.42 [95% CI: 1.04-1.93]), adenosquamous histology (HR, 1.72 [95% CI: 1.18-2.51]), cN1 status (HR, 1.27 [95% CI: 1.02-1.58]), cN2 status (HR, 1.38 [95% CI: 1.14-1.66]), cN3 status (HR, 1.84 [95% CI: 1.19-2.83]), cM1 status (HR, 2.04 [95% CI: 1.42-2.92]) and incomplete resection (HR, 1.45 [95% CI: 1.14-1.84]) all predicted worse survival. Figure 1Table: Baseline characteristics.
There were no significant differences between the groups with regards to sex, race, facility type, and clinical T and M status.Variable Right-sided (n=740) Left-sided (n=912) p Induction chemoradiation 461 (62%) 584 (64%) 0.47 Age (median, IQR) 59 (52-66) 60 (52-67) 0.07 Charlson/Deyo Comorbidity Score 0.02 0 518 (70%) 610 (66%) 1 190 (26%) 243 (27%) 2 32 (4%) 68 (7%) Histology 0.02 Adenocarcinoma 227 (37%) 243 (32%) Squamous 310 (50%) 450 (59%) Large cell 28 (5%) 19 (2%) Adenosquamous 20 (3%) 21 (3%) Neuroendocrine/carcinoid 4 (1%) 7 (1%) BAC 28 (5%) 23 (3%) Clinical N < 0.01 0 190 (27%) 269 (31%) 1 134 (19%) 187 (21%) 2 368 (52%) 381 (44%) 3 16 (2%) 34 (4%)
Conclusion:
In this population analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure. These findings can be used in the risk/benefit analysis when considering patients for pneumonectomy following induction therapy.
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.05 - Immunophenotyping of Circulating T Cells and TILs with Chemotherapy and Phased Ipilimumab in Non-Small Cell Lung Cancer (ID 2787)
17:05 - 17:10 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
Ipilimumab (Ipi) is a humanized CTLA-4 antibody that blocks binding of CTLA-4 with its cognate ligands, permitting T cell activation through CD28 binding. There is evidence that phased in Ipi added to chemotherapy (C) may enhance efficacy in non-small cell lung cancer NSCLC. This trial was undertaken to gain a better understanding of the changes that occur in T cells, regulatory T cells (Tregs), and myeloid-derived suppressor (MDSC) in both the blood and tumor micro-environment with CTLA-4 blockade.
Methods:
Patients with stage T > 4 cm and/or N1, N2 NSCLC were offered neoadjuvant carboplatin AUC6 plus paclitaxel 200 mg/m[2] every 21 days 3 cycles with ipilimumab 10 mg/kg day 1 cycles 2 and 3. Blood for immune profiling of circulating T cells was collected prior to cycle 1, after cycle 1 chemotherapy alone, and after cycle 3 chemotherapy plus Ipi. If patients underwent tumor resection and excess tumor was available, viable tumor infiltrating lymphocytes (TILS) were disaggregated and stored for later analysis. Phenotypic and functional polychromatic flow cytometry (PFC) analyses were performed on peripheral blood mononuclear cells (PBMC).
Results:
Blood was successfully collected at all 3 time points for the first 17/18 patients who initiated trial therapy. Excess tumor (0.96-5 gms) was collected on 5 patients and ample viable CD45+ TIL cells (9.4-26x10[6]) were isolated and viably cryopreserved. Phenotypic analyses revealed that both CD4+ and CD8+ cells from all 17 patients were highly activated following two cycles of ipilimumab (cycle 3) as evidenced by greatly increased frequencies of CD28, HLA-DR, PD-1, and intracellular CTLA-4 expressing cells. The frequencies of Tregs, defined by CD4+CD25+FoxP3+ expression, were highly variable among the 17 participants, with 8 showing increased Tregs, 7 showing decreased frequencies, and 2 remaining unchanged over the course of therapy. Seven of the 17 participants had levels of MDSC cells at or above 5%, with two patients achieving MDSC levels of 13% and 26.7%. Tumor associated antigen (TAA)-specific CD4+ or CD8+ cells were detected at baseline on 4 patients (24%), but their relative frequencies were unaltered by Ipi therapy. The most commonly recognized TAA was Survivin, followed by MAGEA3 and PRAME. No patients developed detectable de novo TAA reactivities while on Ipi therapy. We will report the phenotypic and functional parameters of TILs isolated from 5 tumors of the patients enrolled on the current trial at the time of presentation.
Conclusion:
TAA-specific CD4+ or CD8+ cells were unexpectedly detected in the blood at baseline in a subset of patients. We were able to determine what common NSCLC antigens the circulating CD4+ or CD8+ T cells were activated against, and this has the potential to be a blood based biomarker for trials studying immunotherapy such as vaccines. Neoadjuvant ipilimumab therapy neither facilitated the development of anti-TAA reactivities nor enhanced the frequencies of existing TAA-reactive T cells in PBMC. Neoadjuvant ipilimumab therapy effectively enhanced the frequencies of highly activated T cells, but had no consistent effect of the frequencies of Tregs.
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.03 - Survival after Surgery for pN1 and pN2 Small Cell Lung Cancer: A Comparison with Surgical Treatment of Non-Small Cell Lung Cancer (ID 3100)
18:40 - 18:45 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
With the advent of modern chemotherapy and radiotherapy, we hypothesize that patients who undergo surgery followed by adjuvant therapy for locally advanced small cell lung cancer (SCLC) may have significantly better long-term survival compared to historical data suggesting 2-year overall survival of 4-20% for patients undergoing surgery for SCLC.
Methods:
Prospectively-collected perioperative outcomes and survival data of patients with pathologic T1-3, N1 and (limited) N2 SCLC and non-small cell lung cancer (NSCLC) who underwent complete resection with adjuvant chemotherapy ± radiation and no induction therapy were reviewed from the US National Cancer Data Base from 2003-2011 using Kaplan-Meier method and propensity-score matching. Groups were matched for common prognostic co-variates including year of diagnosis, age, sex, race, education, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, T and N status, tumor size, and tumor location. These prospective data were acquired by certified tumor registrars and include over 70% of cancer diagnoses annually in the U.S.
Results:
During the study period, 369 and 12,152 patients underwent complete resection for pathologic T1-3 N1-2 M0 SCLC and pT1-3 N1-2 M0 NSCLC, respectively. Median follow-up time was 43 months. Five-year overall survival was 37% for SCLC pN1 patients and 26% for SCLC pN2 patients (Table). Matched patients with pN1/N2 NSCLC had better 5-year survival compared to patients with pN1/N2 SCLC (Table and Figure). Figure 1 Figure 2
Conclusion:
SCLC T1-3 N1-2 patients who undergo complete resection followed by adjuvant chemotherapy ± radiation have 5-year survival greater than 26%. Compared to NSCLC, SCLC patients with N1/N2 disease have worse survival; however, the differences in survival between NSCLC and SCLC patients with N1/N2 disease are much smaller than previously reported. These results support a re-evaluation of the role of surgery in multimodality therapy for locally advanced small cell lung cancer.
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.06 - Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management (ID 3089)
11:59 - 12:10 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
With the advent of modern chemotherapy, patients previously thought to have unresectable small cell lung cancer (SCLC) may have tumors amenable to surgery. This study was undertaken to test the hypothesis of whether surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC.
Methods:
Overall survival (OS) of patients with pT1-2 pN1-2 M0 SCLC who underwent non-operative management (chemotherapy ± radiation) vs surgery (with adjuvant chemotherapy ± radiation) in the National Cancer Data Base (NCDB) from 2003-2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic co-variates (year of diagnosis, age, sex, race, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, pathologic T and N status, and tumor location). NCDB data is prospectively collected by certified tumor registrars and include over 70% of cancer cases diagnosed annually in the U.S.
Results:
Of 1,071 patients who met inclusion criteria, 359 (33.5%) patients underwent surgery with adjuvant chemotherapy ± radiation and 712 (66.5%) underwent non-operative management. After propensity-score matching, 11 covariates were balanced between the surgery (n=231) and non-operative (n=231) groups. Surgery was associated with a significantly higher OS than non-operative management (5-year OS 28.1% vs 18.3, log-rank p<0.01) (Figure 1). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to patients with no comorbidities; surgery remained significantly associated with a higher OS than non-operative management (5-year OS 32.1% vs 21.8%, log-rank p<0.01) (Figure 2). Figure 1 Figure 2
Conclusion:
In a propensity-matched analysis of a national population-based cancer database, surgery followed by adjuvant chemotherapy ± radiation for SCLC pT1-3 pN1-2 patients had improved outcomes when compared to non-operative medical treatment. These results support an increased role of surgery in multimodality therapy for more advanced limited-stage small cell lung cancer.
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ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 2
- Moderators:M. de Perrot, J. Mitchell
- Coordinates: 9/09/2015, 16:45 - 18:15, 601+603
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ORAL35.01 - Surgical Approach and Disease Recurrence in NSCLC Patients in the MAGRIT Study (ID 318)
16:45 - 16:56 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
Surgical resection is the standard treatment for early stage Non-Small Cell Lung Cancer (NSCLC). Anatomical resection with lymphadenectomy is recommended in surgically treated patients with Stage I-IIIA NSCLC. Whether mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS) should be performed remains controversial, and there is currently no consensus within the literature. We describe surgical approaches and patterns of disease recurrence in patients enrolled in MAGRIT: a large global randomized study of the MAGE-A3 Cancer Immunotherapeutic versus placebo after complete tumor resection (Phase III trial, MAGRIT, NCT00480025).
Methods:
Study participants were aged ≥18 years, with histologically-proven, MAGE-A3-positive Stage IB, II or IIIA NSCLC (AJCC 6.0) who had undergone R0 anatomic resection of their tumor (lobectomy or pneumonectomy) with mediastinal lymphadenectomy. Patients were randomized to MAGE-A3 or placebo in a 2:1 ratio. A total of 2,272 patients were treated at 556 centers in 34 countries. Because MAGRIT did not demonstrate efficacy overall, and because the number of recurrences in the placebo arm was small (n=271), recurrence patterns by surgical technique are presented in the overall population. An analysis of the placebo population was also conducted as the overall population results are subject to potential bias (a limited treatment effect in small sub-groups cannot be excluded). Cox regression models were used to explore whether lymphadenectomy procedure could be prognostic for disease-free survival (DFS) or overall survival (OS).
Results:
In the total treated population, 76% were men, 52% had squamous cell carcinoma, and 52% received adjuvant chemotherapy. More than half (57%) of patients were enrolled in Europe, with 23% in East Asia, 16% in North America and 4% in other countries. 47% of patients had Stage IB, 6.5% IIA, 30% IIB, and 17% IIIA disease. Lobectomy (including bi- and sleeve-lobectomy) was performed in 85% of patients, and 14% required pneumonectomy. MLNS was performed in 53% and MLND in 47% of patients. MLNS and MLND patients had a similar disease stage distribution. By region, the percentage of patients who underwent MLNS was: 36% in Europe, 65% in East Asia, 94% in North America and 59% in other countries. Among patients who had undergone MLNS or MLND, 37% (n=447/1202) and 36% (379/1067) developed recurrent disease, respectively. Loco-regional recurrence was observed in 40% (177/447) of patients after MLNS and 31% (118/379) after MLND, with distant recurrence observed in 55% (244/447) and 64% (244/379), respectively. There was no difference in the pattern of distant metastases between patients who had MLNS or MLND. Cox modeling showed no impact of the extent of lymphadenectomy on either DFS or OS. A separate analysis of patients in the placebo arm demonstrated similar trends to those of the total study population.
Conclusion:
Lobectomy (including bi- and sleeve-lobectomy) was the most frequently used treatment for patients who participated in the MAGRIT study. Important regional differences in lymphadenectomy were observed. Although the patterns of recurrence varied to some extent with the type of lymphadenectomy, our study did not demonstrate any prognostic impact related to the type of lymphadenectomy performed.
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ORAL35.02 - Wedge Resection vs Segmentectomy for Patients with T1A N0 Non-Small Cell Lung Cancer (ID 3208)
16:56 - 17:07 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
A previous study of the Society of Thoracic Surgeons database showed that non-anatomic resection had lower perioperative morbidity than segmentectomy for non-small cell lung cancer (NSCLC); however the study lacked long term outcomes. We tested the hypothesis that segmentectomy for stage T1a N0 NSCLC had better long-term survival than wedge resection using the U.S. National Cancer Data Base (NCDB).
Methods:
Perioperative outcomes and overall survival (OS) of patients with clinical T1a N0 NSCLC who underwent wedge resection or segmentectomy in the NCDB from 2003-2011 were assessed using propensity-score-matched analysis. Groups were matched for common prognostic covariates (year of diagnosis, race, sex, age, education, income, insurance status, facility type, distance from facility, Charlson/Deyo comorbidity score, tumor size and location). Additional propensity-matched analyses were performed on patients with tumors ≤ 1 cm, patients with no comorbidities, and patients with pathologic T1a pN0 disease.
Results:
Of 40,058 clinical stage T1a N0 NSCLC patients, wedge resection and segmentectomy were performed in 7,517 (19%) and 1,268 (3%) patients, respectively. After matching, all baseline covariates, including comorbidity scores, were balanced between the wedge (n=1,231) and segmentectomy (n=1,231) groups. There were no significant differences between wedge and segmentectomy regarding 30-day mortality (1.6% [n=20] vs 1.5% [n=18], p=0.94). However, wedge was associated with significantly lower long-term survival than segmentectomy (Figure 1); this finding remained consistent even in a propensity-matched analysis of patients with tumors ≤ 1 cm (5 year OS: 56.8% [wedge] vs 78.2% [segmentectomy], log-rank p<0.01). To minimize treatment selection bias due to comorbidities, a propensity-matched analysis was also performed between wedge (n=509) and segmentectomy (n=509) for patients without comorbidities; wedge resection was associated with worse survival when compared with segmentectomy (5 year OS: 65.5% vs 69.5%, log-rank p<0.01). An additional propensity-matched analyses demonstrated that wedge (n=1,099) was associated with worse survival when compared with segmentectomy (n=1,099) for patients with pathologic T1a pN0 disease (5 year OS: 56.8% vs 65.5%, log-rank p<0.01).Figure 1
Conclusion:
In an analysis of a population-based dataset, a large proportion of patients was found to have received wedge resection for stage T1a N0 NSCLC. Segmentectomy for T1a N0 NSCLC had similar 30-day mortality but improved long-term survival when compared to wedge resection, even for patients with very small tumors ≤ 1 cm, for patients with no comorbidities and for patients with pathologic T1a pN0 disease.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-021 - Impact of Radiation on Recurrence Patterns and Survival for Patients Undergoing Lobectomy for Stage IIIA-pN2 Non-Small Cell Lung Cancer (ID 2425)
09:30 - 09:30 | Author(s): D. Harpole
- Abstract
Background:
There is controversy regarding the optimal multimodality treatment strategy for stage IIIA-pN2 non-small cell lung cancer (NSCLC). This study evaluated the impact of induction and adjuvant radiation on locoregional and distant recurrence and survival when induction chemotherapy and surgery is used.
Methods:
Cancer recurrence and survival of 113 consecutive patients who were treated with lobectomy after induction chemotherapy ± radiation for pathologically staged IIIA-N2 NSCLC between 1995 and 2012 at a single institution were evaluated using Kaplan-Meier, logistic regression, and Cox proportional hazard analysis.
Results:
Induction radiation was used in 58 (51%) patients and adjuvant radiation was used in 29 (26%) patients (Table 1). For the entire cohort (n=113), median survival was 30.1 months (95% CI, 22.0 to 56.4). Five-year overall and recurrence-free survivals were 39.0% (95% CI, 29.1 to 48.7) and 28.2% (95% CI, 18.0 to 39.2), respectively. Recurrent disease occurred in 62 (55%) patients after a median (IQR) time of 11.5 months (4.3, 18.7) after surgery. First recurrence site was locoregional only (n=19), distant only (n=34), and locoregional and distant (n=9) (Table 1). In multivariable analysis, induction radiation was associated with decreased likelihood of developing locoregional recurrence (odds ratio (OR), 0.17; 95% CI: 0.04-0.90; p=0.04) but not improved survival (hazard ratio [HR], 1.47; 95% CI: 0.71-3.03; p=0.04) while adjuvant radiation was not associated with decreased likelihood of developing locoregional recurrence (OR, 0.48; 95% CI: 0.07-3.37; p=0.46) but was associated with improved survival (HR, 0.20; 95% CI: 0.04-0.91; p=0.04) (Table 2). Figure 1 Figure 2
Conclusion:
A significant number of recurrences in stage IIIA-pN2 NSCLC patients who undergo induction therapy followed by lobectomy are locoregional recurrences. Use of radiation was associated with improved local control only in the induction setting and may be optimal in terms of survival when given in the adjuvant rather than induction setting.
