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Jin-Soo Lee

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    GR01 - Whether and How to Adapt Treatment of NSCLC Oligometastatic Disease to… (ID 29)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Oligometastatic NSCLC
    • Presentations: 5
    • Now Available
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      GR01.01 - Definition and Minimal Staging in Oligometastatic Disease (Now Available) (ID 3298)

      13:30 - 15:00  |  Presenting Author(s): Anne Marie Clasina Dingemans

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastatic non-small cell lung cancer (NSCLC) is perceived as a separate entity of metastatic NSCLC with limited metastatic potential and possibility of long term survival when treated with local radical treatment1-3. However, uniform definition of oligometastatic NSCLC does not exist. We showed in a recent systematic review (21 papers) that the number of metastasis, allowed in the definition of oligometastatic NSCLC, varies between 1 and 8, in only 2 out of 21 papers > 5 metastasis were allowed4. This has led to an European Organisation on Research and Treatment of Cancer (EORTC) –Lung Cancer Group (LCG) initiative to formulate a consensus definition of synchronous oligometastatic NSCLC. A pan-European multidisciplinary consensus group was established. Results from the systematic review, a European survey and real patient cases were taken into account when. It was concluded that the definition of synchronous oligometastatic NSCLC is relevant when a radical treatment is technically feasible for all tumor sites with acceptable toxicity, that may modify the disease course leading to long-term disease control. Based on the review, a maximum of 5 metastases and 3 organs is proposed. Mediastinal lymph node involvement is not counted as a metastatic site5.

      In addition staging with PET-CT and imaging of the brain is mandatory. This is in line with the advice of the EORTC-imaging group6.

      The eligibility criteria of recent and ongoing clinical trials in this setting will be discussed in this presentation.

      1. Gomez D, Tang C, Zhang J, et al. Local Consolidative Therapy (LCT) Improves Overall Survival (OS) Compared to Maintenance Therapy/Observation in Oligometastatic Non-Small Cell Lung Cancer (NSCLC): Final Results of a Multicenter, Randomized, Controlled Phase 2 Trial. ASTRO 2018 2018;abstract LBA3.

      2. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The lancet oncology 2016;17:1672-1682.

      3. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA oncology 2018;4:e173501.

      4. GiajLevra N, Levra MG, Durieux V, et al. Defining synchronous oligometastatic non-small cell lung cancer: a systematic review. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2019.

      5. Dingemans A, Hendriks L, Berghmans T, et al. MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts WCLC 2018. Toronto: 2018:abstract MA 25.02.

      6. deSouza NM, Liu Y, Chiti A, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. European journal of cancer 2018;91:153-163.

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      GR01.02 - Local Stage of the Primary Disease? (Now Available) (ID 3299)

      13:30 - 15:00  |  Presenting Author(s): Valerie W. Rusch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR01.03 - Nodal Status of the Primary Disease? (Now Available) (ID 3300)

      13:30 - 15:00  |  Presenting Author(s): David Ball

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastases from non-small cell lung cancer (NSCLC) can be classified as synchronous, which are diagnosed at the same time as the locoregional disease, or metachronous, developing after (successful) treatment of the locoregional disease. The title of this presentation implies that the nodes are present at the time of treatment, so the focus will be restricted to the treatment of synchronous oligometastases. In the absence of a universally accepted definition of oligometastatic disease we will assume that the term can be used where there are up to five metastatic sites.

      Nodal involvement as a prognostic factor in patients with oligometastatic disease.

      The earliest reports of attempting to improve survival outcomes for patients with limited metastastic disease were in patients with brain metastases either by resection (1) or by resection or stereotactic radiosurgery (2). Five year survivors were observed, vindicating aggressive treatment in this subset of stage IV patients with NSCLC, but patients with regional node involvement appeared to have worse survival than patients with N0 disease. This was confirmed in a subsequent large multicentre individual patient data meta-analysis reported by Ashworth et al of 757 patients who were treated with ablative treatments to all sites of disease (3). Factors that were important for survival in the meta-analysis were metachronous versus synchronous and histology (favouring adenocarcinoma) as well as N stage. Using recursive partitioning analysis, Ashworth et al were able to group patients with synchronous metastases into an intermediate risk group with N0 disease and a 5 year survival of 36.2% versus a high risk group with N1 or N2 disease and a 5 year survival of 13.8%. Why should regional node status be a prognostic factor in patients who already have distant metastatic disease? Most likely it is because nodal involvement is a surrogate for the volume of metastatic disease that may have been underestimated in the pre-PET era.

      Is regional nodal involvement a contraindication to an aggressive approach?

      Although Hu et al (2) recommended against an aggressive approach to the locoregional disease in patients with stage II or III NSCLC, the fact that 3 year survivors were observed in their cohort and 5 year survivors in the meta-analysis suggests that it is an option that should be discussed considered. in a retrospective study by Flannery et al if the thoracic disease was not treated definitively, survival at 5 years was 0% compared with 34.6% for surgical resection or chemoradiation (P < 0.0001) (4). Patients with N0 or N1 disease (grouped together) had longer survival than patients with N2 or N3 disease, but this was not statistically significant. A prospective phase II trial treated patients with up to 5 oligometastatic sites with chemotherapy followed by chemoradiation to the primary and involved nodes plus SABR or high dose radiotherapy (60 Gy in 30 fractions) to the metastases was associated with a median survival of 28 months, but there was no difference in survival whether nodes were or were not involved (5).

      Does nodal status influence whether locoregional disease should be treated by surgery, SABR or (chemo)radiotherapy?

      This will depend on the patient’s fitness for surgery, and the anatomical extent and location of disease. We have no evidence to support any one strategy. We use the same principles to select treatment to the locoregional disease as if there were no oligometastatic disease present. In the Ashworth meta-analysis, surgical management of the primary was a favourable prognostic feature with a hazard ratio of 0.74 (95% CI: 0.55 – 1.00) on univariable analysis, but not on multivariable analysis (3). In the first randomized trial in patients with NSCLC oligometatases the use of ablative treatments did improve disease free survival in patients with NSCLC who had up to 3 metastases and no evidence of progression after systemic therapy.(6) In this small trial, nearly all patients had synchronous oligometastases. Treatments used for the primary disease after first-line systemic therapy included surgery, stereotactic ablative body radiotherapy (SABR) and chemoradiation. Any involved regional nodes were regarded collectively as one “oligometastatic site”. There was no significant difference in progression-free survival comparing patients with N0-1 disease versus N2-3.

      Conclusion

      Where a patient has synchronous oligometastatic disease that is amenable to ablative therapy, definitive treatment to the primary site and any involved regional nodes taking into account the patient’s general condition and disease stage is a reasonable option, regardless of nodal stage.

      References

      1. Billing PS, Miller DL, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Surgical treatment of primary lung cancer with synchronous brain metastases. J Thorac Cardiovasc Surg. 2001;122(3):548-53.

      2. Hu C, Chang EL, Hassenbusch SJ, 3rd, Allen PK, Woo SY, Mahajan A, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106(9):1998-2004.

      3. Ashworth AB, Senan S, Palma DA, Riquet M, Ahn YC, Ricardi U, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer. 2014;15(5):346-55.

      4. Flannery TW, Suntharalingam M, Regine WF, Chin LS, Krasna MJ, Shehata MK, et al. Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery. Int J Radiat Oncol Biol Phys. 2008;72(1):19-23.

      5. Petty WJ, Urbanic JJ, Ahmed T, Hughes R, Levine B, Rusthoven K, et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2018;102(3):527-35.

      6. Gomez DR, Blumenschein GR, Jr., Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-82.

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      GR01.04 - The Rationale for Local Consolidative Therapy in Oncogene-driven, Oligo-and Poly-metastatic NSCLC (Now Available) (ID 3301)

      13:30 - 15:00  |  Presenting Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR01.05 - Site of Oligometastases (Now Available) (ID 3302)

      13:30 - 15:00  |  Presenting Author(s): Paul Van Schil

      • Abstract
      • Presentation
      • Slides

      Abstract

      The concept of oligometastatic disease representing patients with only a few or “oligo”metastases, is a relatively new entity in thoracic oncology and surgery [1-2]. Most probably, an intermediate state exists between patients with locoregional disease without distant metastases and those with multiple metastatic involvement in one or more distant organs.

      The International Association for the Study of Lung Cancer (IASLC) adopted this concept and in the 8th Tumor-Node-Metastasis (TNM) edition a new category was introduced representing those patients with a single metastasis in a single distant organ, currently M1b involvement [3]. These patients belong to stage IVA, as well as patients with contralateral malignant nodules. In contrast, multiple metastases in a single or multiple distant organs are currently described as M1c disease, and they are grouped together in the new stage IVB category. In the IASLC database patients with clinical stage IVA disease had a median survival time (MST) and 5-year survival rate of 11.5 months and 10%, respectively, in contrast to 6.0 months and 0% for patients with stage IVB disease [4].

      No consensus exists on the precise definition of oligometastatic disease. For this reason the European Organisation of Research and Treatment of Cancer (EORTC) created a task force to propose a definition of synchronous oligometastatic disease based on consensus by thoracic oncology experts [5]. A maximum of 5 metastases and 3 organs is proposed. Diffuse serosal metastases (meningeal, pericardial, pleural, mesenteric) as well as bone marrow involvement are not accepted as specific site as these cannot be treated with radical intent.

      Is the specific organ involved important in management and prognosis of these patients? Patients with contralateral lung nodules, brain, bone and adrenal metastases are mostly reported in literature as these organs are quite accessible for local ablative treatment by surgical excision or stereotactic radiotherapy. For patients with bilateral / contralateral tumor nodules introduced in the IASLC prospective database by the electronic data capture (EDC) system, MST was 12 months, quite similar to patients with ipsilateral pleural/pericardial effusion. Although the numbers were quite small, for those patients with a single adrenal metastasis introduced by EDC, MST was 6.5 months, for a single bone metastasis 12.6 months, and for a single brain metastasis 12.1 months [3]. These survival times were significantly better than those for patients with multiple lesions at a single site. In general, most survival data are from retrospective series with an inherent selection or publication bias. For this reason, the EORTC decided not to consider the specific organ involved but this may change when more prospective data become available.

      Are there any predictive factors for survival in patients with oligometastatic disease? In an individual patient data meta-analysis of 757 patients with 1-5 synchronous or metachronous metastases from non-small cell lung cancer (NSCLC), predictive factors were synchronous versus metachronous metastases, N stage and adenocarcinoma histology [6]. Surgery was the most frequently used treatment, as well for the primary tumor as for the metastatic involvement. Low-risk patients had metachronous metastases, the intermediate risk group presented with synchronous metastases and N0 disease, and the high-risk group with synchronous disease and thoracic lymph node involvement. So, adequate lymph node staging should be performed in every patient [7].

      May combined modality therapy including locoregional ablative treatment by stereotactic radiotherapy or surgery improve prognosis in patients with oligometastatic disease? A recent landmark trial investigated the role of local ablative therapy in patients with stage IV NSCLC with three or fewer metastases remaining after first-line systemic therapy [8]. In this multicentre, controlled phase II study 49 patients were randomized between local consolidative therapy group consisting of surgery, radiotherapy or a combination with the aim of ablating all residual disease, and maintenance treatment which was chosen from a predefined list of regimens approved by the Food and Drug Administration (FDA). Primary endpoint was progression-free survival. Secondary outcomes were overall survival, safety and tolerability, time to progression of previous metastatic lesions, time to appearance of new metastatic lesions, and quality of life. Most frequent metastatic sites were brain, bone, adrenal gland, pleura and metastatic lung lesions. Significantly longer progression-free and overall survival rates were noted in the local consolidative therapy group than in the maintenance treatment group. Time to the appearance of a new lesion was longer among patients in the local consolidative therapy group than among patients in the treatment group. Survival after progression was also longer in the local consolidative group [8].

      Regarding specific management of oligometastatic disease related to the site of involvement, the European Society of Medical Oncology (ESMO) recently published clinical practice guidelines for metastatic NSCLC including oligometastatic disease [9]. In the presence of a solitary metastatic site on imaging studies, efforts should be made to obtain a cytological or histological confirmation of stage IV disease. Stage IV patients with one to three synchronous metastases at diagnosis may experience long-term disease-free survival following systemic therapy and local consolidative therapy (high-dose radiotherapy or surgery). Because of the limited evidence, these patients should be discussed within a multidisciplinary tumor (MDT) board and inclusion in clinical trials is preferred. Although operative risk is low and long-term survival may be achieved, current evidence for surgery in oligometastatic disease is limited, and the relative contribution of surgery versus radiotherapy as local treatment modality has not been established yet. Solitary lesions in the contralateral lung should, in most cases, be considered as synchronous secondary primary tumors and, if possible, treated with curative-intent therapy [9].

      Finally, even salvage surgery may be considered in highly selected patients with oligometastatic disease to improve long-term outcome [10].

      REFERENCES

      1. Pfannschmidt J. Lung Cancer. 2010;69:251-8

      2. Shields' General Thoracic Surgery, 8th edition 2019, pp. 1289-90

      3. Eberhardt WE. J Thorac Oncol. 2015;10:1515-22

      4. Goldstraw P. J Thorac Oncol 2016; 11:39-51

      5. Dingemans AM. IASLC 19th WCLC 2018; abstract MA25.02

      6. Ashworth AB. Clin Lung Cancer 2014;15:346-55

      7. Fernandez R. J Thorac Dis 2019; 11(Suppl.7):S969-S975

      8. Gomez DR. J Clin Oncol 2019 May 8; doi:10.1200/JCO.19.00201

      9. Planchard D. Ann Oncol 2018; 29(Suppl. 4):iv192-iv237

      10. Duchateau N. Ann Thorac Surg 2017;103:e409-e11.

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