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P. Bonomi

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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)

      14:20 - 14:40  |  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)

      14:40 - 15:00  |  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)

      15:00 - 15:20  |  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)

      15:20 - 15:40  |  Author(s): R.D. Timmerman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 04 - Clinical Care of Lung Cancer (ID 102)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI04.07 - Changes in Skeletal Muscle Index and Body Mass Are Prognostic Factors in First Line Stage IV Non-Small Cell Lung Cancer (NCSCL) Patients (ID 3091)

      17:20 - 17:25  |  Author(s): P. Bonomi

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancer cachexia is a complex metabolic syndrome affecting 60-80% of patients with non-small cell lung cancer (NSCLC). The characteristic involuntary weight loss observed in cachexia is associated with poor outcomes in advanced NSCLC; however, reduced muscle mass may be a more reliable prognostic indicator. In this study, we examine the impact of changes in weight and skeletal muscle index (SMI) in the first 12-weeks of therapy on clinical outcome parameters for front line stage IV NSCLC patients.

      Methods:
      Cancer cachexia is a complex metabolic syndrome affecting 60-80% of patients with non-small cell lung cancer (NSCLC). The characteristic involuntary weight loss observed in cachexia is associated with poor outcomes in advanced NSCLC; however, reduced muscle mass may be a more reliable prognostic indicator. In this study, we examine the impact of changes in weight and skeletal muscle index (SMI) in the first 12-weeks of therapy on clinical outcome parameters for front line stage IV NSCLC patients.

      Results:
      119 patients had serial weights available and were included for analysis: 49% were male, median age of males was 71, and females were 63 years; 82% had smoking history. Histology was predominantly adenocarcinoma and squamous (62% and 22%). Median PFS was 159 days, and medial OS was 314 days. Median weights for males at baseline, 6 weeks, and 12 weeks were 77.3, 76.9, and 77.3 kilograms respectively. Median weights for females at baseline, 6 weeks, and 12 weeks were 67.1, 66.7, 65.8 kilograms respectively. Baseline weights were less for women than men (p<0.0007) but the change in weight with time was not significantly different at measured time points. Weight loss of greater than 10.39 pounds in the first six weeks of treatment was strongly associated with inferior outcomes (PFS 2.35 vs. 6.44 months, p=2.02 x 10[-7]; OS 3.96 vs. 15.48 months, p=8.71 x 10[-9]). Persistent weight loss at 12 weeks was also associated with worse outcomes (PFS p=1.72x10[-7 ], OS p= 0.00286). Within this cohort, 41 patients had baseline SMI measured from their CT scans, 27 patients had additional CT-derived SMI available at 6- and 12- weeks. Patients with SMI decrease at 12 weeks of at least 2.6 units (n=9, 33%) had an inferior median PFS compared with those not meeting this threshold (2.79 months vs. 9.75 months p<0.05). In a multivariate analysis, this loss, when adjusted by gender, remained significantly associated with PFS (HR=2.37, p < 0.05).

      Conclusion:
      This study shows the prognostic value of weight loss for progression on first line chemotherapy as early as six weeks following therapy initiation. This analysis confirms the significant association between weight loss on serial measurements and inferior survival in stage IV NSCLC pts. Additionally, this is the first report of decreasing CT-derived SMI correlating with inferior progression free survival on front line platinum doublet therapy for NSCLC.

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    MINI 29 - Meta Analyses and Trial Conduct (ID 156)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI29.03 - Prognostic Value of Biomarkers Associated with Glucose Metabolism and Systemic Inflammation in Advanced On-Small Cell Lung Cancer (NSCLC) (ID 3061)

      18:40 - 18:45  |  Author(s): P. Bonomi

      • Abstract
      • Presentation
      • Slides

      Background:
      Alterations in glucose metabolism and appetite stimulating hormones have been correlated with inflammation but there is little information on frequency and prognosis in newly diagnosed stage IV non-small cell lung cancer (NSCLC) This study objective was to identify associations of circulating biomarkers of glucose metabolism and inflammation with prognosis in pre-treatment sera from stage IV NSCLC patients selected for platinum doublet based chemotherapy.

      Methods:
      Pretreatment serum from 118 Pts with frontline stage IV NSCLC were evaluated with the Bio-Plex Pro Human Diabetes Assay panel (adiponectin, adipsin, c-peptide, ghrelin, gastrin inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, IL-6, insulin, leptin, Plasminogen activator inhibitor-1, resistin, TNFα, vistatin) and HSTCMAG-28SK | MILLIPLEX MAP Human High Sensitivity T Cell Panel - Immunology Multiplex Assay (Fractalkin, GM-CSF, IFNγ, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, ITAC, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-3α, TNFα) on a FlexMAP 3D system (Luminex Corp.). Pts were treated with standard platinum doublets based chemotherapy. Associations of biomarkers with progression free and overall survival (PFS,OS) outcomes were assessed using multivariate Cox PH analyses.

      Results:
      Most patients had metabolic levels below the prognostic threshold. However, high levels of insulin, GIP, glucagon, visfatin, ghrelin, GLP-1 were significantly associated (p<0.05) with shorter PFS. Low levels of adipisin (deficiency of which is associated with obesity) was associated with shorter PFS (p=.0185). High levels of pro-inflammatory markers: ITAC, GM-CSF, Fratalkine, INF-ϒ, IL-12p70, IL-13, IL17A, IL-4, IL-23, IL8.4, MIP-α, MIP-1 were also associated with poor PFS (p<0.05) (See Table I for more details on select biomarkers) High levels of these endocrine markers (except insulin and GIP) were associated with shorter OS as were ITAC, GMCSF, IL12p70, IL-13, IL4, IL23, IL5 (p<0.05). Table I. Biomarker correlation with progression free survival

      Marker Cutoff-pg/mL N < N > Median PFS < Median PFS> Logrank p
      Insulin 1004.9 82 36 6.08 4.04 0.026161
      Glucagon 361.2 110 8 5.46 1.71 0.010219
      Visfatin 8298.3 109 9 5.65 1.45 8.77E-06
      Ghrelin 2897.2 104 14 6.02 2.12 0.009423
      GLP.1 268.8 109 9 5.65 1.97 0.000618
      ITAC 104.7 99 19 5.82 2.96 0.012529
      Fractalkine 271.7 97 21 6.08 3.16 0.0067
      IL.12.p70. 17.0 109 9 5.65 3.16 0.010631
      IL.13 14.9 105 13 5.82 2.76 0.001533
      IL.17A 49.4 102 16 5.82 3.65 0.004862
      IL.4 66.1 104 14 6.02 2.96 0.000917
      IL.8.4 3.0 25 93 12.8 4.8 0.008985


      Conclusion:
      Imbalances in the glucose metabolism pathway and increased levels of pro-inflammatory circulating markers were uncommon but consistently associated with a poor prognosis in stage IV NSCLC patients early in their treatment cycle. Alterations in these systems have been associated with cancer cachexia and may be targets for intervention in improving prognosis for select patients with NSCLC.

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    MINI 32 - Topics in Localized Lung Cancer (ID 166)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI32.08 - Identification of a Meta-Gene Network Associated with Metformin Sensitivity and Recurrence in Stage I Non-Small Cell Lung Cancer (ID 1727)

      19:10 - 19:15  |  Author(s): P. Bonomi

      • Abstract
      • Presentation
      • Slides

      Background:
      We recently reported an association between progression-free survival and metformin exposure in patients with early stage non-small cell lung cancer (NSCLC). Local recurrence in stage I disease is estimated to be as high as 50% in US populations. Therefore, a method to identify NSCLC patients who are most likely to benefit from metformin treatment has potential clinical relevance.

      Methods:
      Three previously published, publically available gene expression array data sets documenting the effects of metformin treatment on transcriptional activity in human cell lines were used for the initial stages of the present study. These data sets were evaluated individually for enrichment of differentially expressed genes with a gene set analysis related to biological processes also performed. Differentially expressed genes common to all three studies were then used to form a metformin meta-gene. This combined meta-gene was evaluated topologically using a protein-protein interaction database to determine if any gene products had previously observed direct interactions. The metformin meta-gene network was then examined in expression array data sets from stage I NSCLC patients (n=293) assembled from multiple published studies.

      Results:
      We identified several biological themes resulting from metformin treatment, including: immune cell differentiation, response to hypoxia, steroid receptor signaling, alternate splicing, and changes in cellular metabolism. Intersecting the differentially expressed genes from each data set, we identified 105 genes consistently up-regulated and 30 genes consistently down-regulated by metformin treatment, forming a tissue-independent meta-gene for metformin effects. Two networks of interacting genes were identified in this analysis; the first network consisting of 27 genes (22 up-regulated and 5 down-regulated) and the second consisting of three up-regulated genes.This meta-gene was then examined in two independent cohorts of stage I adenocarcinoma. In the first cohort (n=125), patients clustered into two groups when k-means analysis was performed with respect to the 30 genes in the metformin meta-gene network. These patients had a significantly (p=0.014) different incidence of recurrence between the two clusters. This result was independently validated in the second data set (n=168) where patients clustered into two groups and also demonstrated significant stratification of recurrence (HR=1.21; p=0.001).

      Conclusion:
      We have identified a meta-gene of interacting proteins associated with both metformin therapy and recurrence-free survival in early stage lung cancer patients. This suggests a potential method for identifying NSCLC patients most likely to benefit from metformin therapy, and furthermore, identifies mechanistic avenues by which metformin treatment may benefit early stage lung cancer patients.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P1.01-052 - Retreatment with Platinum-Based Regimen for Patients with Metastatic NSCLC Is a Reasonable Therapy (ID 2444)

      09:30 - 09:30  |  Author(s): P. Bonomi

      • Abstract
      • Slides

      Background:
      Standard first-line therapy in stage IV NSCLC patients remains a platinum-based regimen. Currently, there are limited FDA approved agents for second line therapy following progressive disease. The purpose of this study was to evaluate the response to retreatment with platinum-based regimens upon progression in a group of platinum-sensitive patients.

      Methods:
      Patients with stage IV NSCLC previously treated with a platinum-based first-line regimen were retrospectively reviewed. We examined the outcomes of 52 patients retreated with a platinum-based regimen upon progression between February 2002 and March 2015. Patients were evaluated for response rate, progression free survival, overall survival and platinum reactions.

      Results:
      Of the 52 patients reviewed, 31 were women (59.6%) and 21 were men (40.4%). Median age was 62.6 (range 42-89) and adenocarcinoma was the most prevalent histology (86.5%). The response rate for retreatment was 21.15%. A notable 57.69% of patients had stable disease. The median PFS for the first line platinum regimen was 9.2 months (CI 95%; 6.28-12.13) and for the retreatment was 4.8 months (CI 95%; 3.17-6.42). The median OS from diagnosis was 23.31 months (CI 95%; 11.76-34.85). A platinum reaction was noted in 9 of the patients (17.3%) though none were fatal.

      Conclusion:
      Patients with prolonged PFS with frontline chemotherapy appear to benefit from retreatment with a platinum-based regimen. This cohort demonstrated by a PFS of 4.8 months upon retreatment. Patients with prolonged progression free survivals with frontline chemotherapy may be reasonable candidates to consider for retreatment with a platinum-based regimen.

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      P1.01-062 - Rash as a Marker for the Efficacy of Necitumumab in the SQUIRE Study (ID 97)

      09:30 - 09:30  |  Author(s): P. Bonomi

      • Abstract
      • Slides

      Background:
      SQUIRE, a randomized, phase III study (n=1,093), demonstrated that the addition of the EGFR monoclonal antibody necitumumab (N) to gemcitabine-cisplatin (GC) improved overall survival in patients with stage IV squamous NSCLC. Rash is an established class side-effect associated with EGFR-targeting agents. Previous studies have suggested a positive association between rash and clinical outcomes with EGFR-targeted therapy.

      Methods:
      Pre-emptive treatment for rash was not allowed per protocol until completion of the first cycle of study therapy. For the purpose of this analysis, patients randomized to the N+GC arm were categorized and grouped according to whether or not they experienced rash during the first two cycles of study therapy. Patients who died or were lost to follow-up before completing two cycles of study therapy were not included in this analysis. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models, with comparisons between arms using a stratified log-rank test.

      Results:
      505 patients were evaluable in the N+GC arm at the end of cycle 2 of which 69% experienced rash during cycle 1 and/or cycle 2. Patients experiencing rash in the N+GC arm had improved OS (HR=0.738, p=0.0001) and PFS (HR=0.808, p=0.0066) compared with patients in the GC arm. Patients experiencing rash in the N+GC arm had improved OS (HR=0.656, p=0.0001) compared with patients in the N+GC arm who did not experience rash. The difference in PFS between patients in the N+GC arm experiencing rash versus those not experiencing rash was not statistically significant. Median PFS and OS for patients experiencing rash in the N+GC arm was 6.2 mo and 13.6 mo respectively, as compared to 5.6 and 10.2 mo for patients in the N+GC arm without rash and 5.6 and 10.6 mo for patients in the GC arm.

      Patients alive and under follow-up after Cycle 2
      N+GC with rash N=350 N+GC no rash N=155 GC N=508
      Overall Survival, mo (CI) 13.6 mo (11.6, 15.2) 10.2 (8.7, 11.6) 10.6 (9.5, 11.9)
      HR* (95% CI) 0.656 (0.529, 0.813) 0.738 (0.631, 0.864)
      Stratified log-rank p value* 0.0001 0.0001
      PFS, mo (CI) 6.2 mo (5.7, 6.9) 5.6 (5.0, 5.7) 5.6 (5.3, 5.6)
      HR* (95% CI) 0.867 (0.693, 1.084) 0.808 (0.692, 0.942)
      Stratified log-rank p value* 0.2127 0.0066
      *In comparison to the N+GC group with rash

      Conclusion:
      Rash occurring during the first two cycles of treatment with necitumumab (N+GC) is associated with improved OS in patients with advanced squamous NSCLC.

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    P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P2.08-005 - Vinorelbine as Second or Third-Line Therapy in Pemetrexed-Pretreated Malignant Pleural Mesothelioma (MPM) Patients (ID 2403)

      09:30 - 09:30  |  Author(s): P. Bonomi

      • Abstract

      Background:
      There is no standard treatment for patients (pts) with MPM progressing during or after pemetrexed/platinum-based chemotherapy (PBC). Single agent chemotherapy is often administered in everyday practice, although its use is poorly supported by clinical trials. The aim of this retrospective study (NCI01865045) was to analyze the efficacy and toxicity of second (2nd) and third (3rd) line vinorelbine (VNR) in a large cohort of PBC-pretreated MPM patients.

      Methods:
      The clinical records of MPM pts consecutively treated in 8 Italian Centers with intravenous (iv) or oral (po) VNR as 2nd or 3rd line treatment following PBC were reviewed. Radiological response was assessed by modified RECIST criteria. Toxicity was reported according to CTCAEv4 criteria. Relative dose-intensity (DI) of VNR was calculated. Progression-free survival (PFS) and overall survival (OS) were estimated and correlated to clinical variables: age, gender, histological subtype, ECOG performance status (PS), line of VNR therapy (2nd vs 3rd) and outcome of first-line treatment.

      Results:
      From August 2001 to September 2014, 161 pts (M/F 120/41) were treated, 128 with iv and 33 with po VNR. Most of the cases included (92%) were treated after 2007. Histological subtype was epithelioid in 134, biphasic in 15, sarcomatoid in 8 and unspecified in 4 pts. Median age was 67 years (range 41-82). VNR was administered as 2nd or 3rd line treatment in 94 and 67 pts, respectively. Median number of VNR cycles was 3 (range 1-26), median relative DI was 88%. Main grade 3-4 toxicities were neutropenia in 9%, fatigue in 4% and constipation in 5% of pts. No toxic death occurred. A partial response was observed in 10 pts (6%), stable disease in 57 (35%), for an overall disease control rate of 41%. Median PFS and OS were 2.5 and 6.7 months, respectively. In multivariate analysis, only ECOG PS (0 vs 1-2) was significantly associated with improved PFS and OS. An analysis of molecular predictors of VNR response is ongoing.

      Conclusion:
      In this large retrospective patient cohort, 2nd and 3rd line VNR had modest but definite activity in PBC-pretreated MPM patients, with an excellent toxicity profile. Although inclusion in prospective clinical trials of new agents should be always considered in this setting, single agent VNR remains a reasonable option for palliation.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-093 - Neutrophil/Lymphocyte Ratios Inversely Related to Weight Change, Overall Survival; ALI Inversely Related to OS in NSCLC Pts (ID 3078)

      09:30 - 09:30  |  Author(s): P. Bonomi

      • Abstract
      • Slides

      Background:
      A high neutrophil/lymphocyte ratio (NLR) at baseline and at follow-up is associated with shorter survival in cancer patients and may be a surrogate for ongoing inflammation which is implicated in promoting cancer cachexia and tumor progression. The objective of this study is to explore potential relationships between OS, serial weights, and serial NLRs and ALI (Advanced Lung cancer Inflammatory) index in advanced NSCLC patients receiving chemotherapy.

      Methods:
      139 stage III/IV NSCLC pts were treated with first-line platinum doublets from June, 2011 to August, 2012. NLR and body weight were recorded at baseline, 6, and 12 weeks from initiation of therapy and correlated with OS. The association between NLR and OS was assessed using Cox PH analysis, and the association between NLR and weight change was assessed using a simple regression analysis. ALI index was defined as BMI (Body Mass Index) x (Albumin)/NLR. ALI was calculated at baseline, 6, and 12 weeks from initiation of therapy and correlated with OS for some pts.

      Results:
      139 pts with median age 68, PS 0-1/2 = 83/17%, male/ female = 48%/52%. NLR at baseline median 3.6, range 0.1898 to 30.910; at 6wks median 3.11, range 0.2703 to 42.11; at 12wks median 3.52 range 0.2147 to 42.93. Increase in the NLR at baseline, 6, and 12 weeks were associated with a decrease in OS (baseline HR 1.06, p < 0.001; 6 wks HR 1.07, p = 0.001; 12wks HR 1.05, p < 0.001). The effect of NLR on hazard is multiplicative (i.e. a change of 5 in baseline NLR results in a HR of 1.065). Initial weight and NLR were negatively correlated (cor = -0.267, p = 0.001), and weight change and NLR were also negatively correlated at 12wks (cor = -0.371, p < 0.001; weight change -13.17kg to +16.61kg, median -0.5kg, mean -0.89kg). 96, 93 and 84 pts had ALI score available at baseline, 6wks, and 12 wks respectively. 38 pts with baseline ALI score <= 18 had significantly lower OS (median OS=9.63 mos) compared to 58 pts with ALI > 18 (median not reached, p = 0.001). 41 pts with 6 week ALI <= 18 had significantly lower OS (median OS=11.4 mos) compared to 52 pts with ALI > 18 (median not reached, p = 0.03). 30 pts with 12 week ALI <= 18 had significantly lower OS (median OS=9 mos) compared to 54 pts with ALI > 18 (median not reached, p < 0.001).

      Conclusion:
      High baseline and progressive increase in NLRs are associated with inferior OS and weight loss in advanced NSCLC patients. In addition to having prognostic significance, these observations suggest that studying molecular mediators of cachexia/inflammation and their relationships to tumor progression may identify new therapeutic targets in the large subset of NSCLC patients who have cancer cachexia. We also confirmed findings by Jafri at all 2013, that ALI score <=18 is associated with lower OS at any time before or during treatment.

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