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Tomoyuki Hishida

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    CS01 - Controversies in NSCLC OMD (ID 3)

    • Event: WCLC 2019
    • Type: Controversy Session
    • Track: Oligometastatic NSCLC
    • Presentations: 4
    • Now Available
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      CS01.01 - "Hunting a Ghost for 25 Years – Will We Ever Catch OMD?" - No (Now Available) (ID 3144)

      11:00 - 12:30  |  Presenting Author(s): Tom Treasure

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastatic disease (OMD) is no more and no less than what it say on the label. It is cancer with few metastases, no more than can be counted on the fingers of one hand. A few metastases can be locally eradicated with surgery, image guided thermal ablation (IGTA) or with stereotactic ablative radiotherapy (SABR) but beyond five it becomes increasingly impractical to attempt local control. Total eradication is unlikely and systemic treatment makes more sense. So five or fewer identified metastases fit a working definition of OMD as treatable by local interventions.

      'Framing’ disease according to suitability for treatment has always been part of clinical practice. Diagnostic frames shift over time. A classic example is the emergence of 'ESRD' (end stage renal disease) as a diagnosis. 18thC diagnoses depended on clinical descriptions. 'Dropsy’ was illness characterised by water retention; what we call oedema. William Withering observed that some of those sick with dropsy were helped by infusions of foxglove. Later Richard Bright discovered protein in the urine of others. At autopsy he found shrivelled kidneys and dropsy had to be reframed, depending on whether it was the heart or the kidneys that were failing. Aetiology, pathophysiology, and histology sequentially framed the many types of kidney disease through the 1960s but effective treatment only became available with dialysis and transplantation. Long-term survival was possible but was too costly for nearly all individuals and their families. In 1972 US Congress passed Public Law 92-603 which framed a new diagnosis: ESRD. Patients with end stage renal disease were entitled to federal funding. In 1974 ESRD appeared for the first time in PubMed in a paper about public financing. ESRD has been used in titles or abstracts 15,282 times since and runs at over a thousand citations a year.

      Hellman and Weichselbaum proposed the term ‘oligometastases’ in 1995 to describe a clinical state between freedom from metastases and their ‘extensive and widespread’ presence. (Figure) A search for <oligometas*> reveals very few publications for about 10 years. Improving resolution of CT, and then PET imaging, allowed the counting of macroscopic metastases by being more confident of the absence of further macroscopic metastases. That was a prerequisite to diagnose OMD. Weichselbaum had in mind that “recognition ... of a state of oligometastases is necessary to invite active clinical investigation of new and potentially curative therapeutic strategies”. In practical terms it is the therapeutic opportunity that makes OMD a useful working diagnosis, summarised as few enough to 'zap'. In 2015 Joseph Salama surveyed radiation oncologists on their clinical practice and opinions; 99% of 1007 regarded OMD as something for them to treat.

      It is the feasibility of treatment which characterises OMD. Many diseases are framed and reframed by whether they are amenable to treatment. A familiar example was the emergence of non small-cell lung cancer (NSCLC) as a diagnostic frame. In the 1970s, adenocarcinoma, squamous cell, and large cell anaplastic cancer had 25-30% five-year survival after lobectomy, but surgery for small-cell cancers nearly always failed. Conversely chemotherapy for lung cancer, then associated with modest responses, caused small-cell carcinoma to melt away, if only temporarily. It may seem strange to frame a disease by what it is not, but that is how NSCLC was framed. Lung cancer was dichotomised on the basis of response to treatments.

      We used use 'SBE' for subacute bacterial endocarditis and 'CVA' for cerebrovascular accident. In the modern world of heart surgery and antibiotic resistance, SBE is no longer a serviceable diagnostic frame. We must be specific about organisms, underlying lesions, and prostheses. With therapeutic interventions available for stroke we have to distinguish bleeding from embolism. The catch-all term 'CVA' will no longer serve. In time NSCLC will no doubt be unbundled on the basis of tumour markers, genomics, and targeted treatments. But in an era when we talk of precision medicine, it is remarkable that the 99 patients in SABR-COMET had more than five different primary and secondary sites, bundled as OMD.

      At Guy’s our lung cancer meetings were chaired by a lady radiologist who steered us with incisive clarity. She and I discussed treatment of metastases. She was just back from a trip to the US where she had many similar conversations. “It always ends up with the same question” she told me “Can you charge for it?”. So that is the reality. The 1007 radiation oncologists will view the SABR-COMET trial results as the evidence they need. People with ESRD demonstrably survive due to treatment but OMD does no more than identify patients at the tail of the survival distribution, those most likely to live a while longer. Attributing their survival to treatment of a few metastases that can be seen is largely illusory. If sound biological science is the Ghost we seek, we haven't caught it yet.

      nscl omd for iaslc abstract.jpg

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      CS01.02 - "Hunting a Ghost for 25 Years – Will We Ever Catch OMD?" - Yes (Now Available) (ID 3145)

      11:00 - 12:30  |  Presenting Author(s): José Belderbos

      • Abstract
      • Presentation
      • Slides

      Abstract

      The treatment options for NSCLC patients with a limited number of metastases at diagnosis (oligometastatic disease) have increased the past decade. The focus lies at combining systemic- and local radical treatments. With the introduction of oligometastatic disease (OMD) as a separate entity, a more radical treatment approach is increasingly applied. For OMD we distinguish synchronous OMD (in case of OMD at diagnosis) and metachronous OMD (in case of a limited amount of metastases as first event of an initially locally limited disease). There is also the term oligometastatic progression in which case during systemic treatment of a pluri-metastatic disease only few metastases progress. Finally there could be a situation called oligo persistence in case of remaining metastatic lesions. The existing literature is seriously flawed by the lack of consensus on the definition of oligometastatic disease. Often a maximum of 2-3 metastases are referred to as oligometastatic disease, but ≤5 metastases are also selected and considered for radical treatment.

      Important developments of local consolidative therapies in OMD

      Since 2016 several retrospective and prospective trials reported favorable progression free survival (PFS) for OMD treated with systemic therapy followed by local consolidative therapy (LCT). The intrathoracic disease is generally locally treated with radical radiotherapy or resection. Treatment of the metastases consists of radical or stereotactic radiotherapy, surgical resection or local ablative therapies. In an observational study radical local treatment for a selected group of NSCLC patients (n=91) with good performance status presenting with synchronous oligometastatic disease resulted in 14 months PFS and 32 months overall survival (OS).These results are comparable to outcomes for stage III NSCLC disease.

      De Ruysscher et.al. [2] reported a prospective single arm phase II study for synchronous oligometastatic disease treated with radical local treatment (radiotherapy or surgery) after first line chemotherapy. The median PFS and OS in this study were 12.1 months and 13.5 months respectively. After 24 months 15% of the patients did not show disease progression.

      In a trial Iyengar et al [4] randomized 29 metastatic NSCLC patients with up to 6 sites of extracranial disease (including primary) and a good performance. After induction chemotherapy non-progressive patients were randomized for maintenance chemotherapy or stereotactic radiotherapy. In an unplanned interim analysis, the median PFS was 9.7 months in the stereotactic radiotherapy arm versus 3.5 months in the maintenance chemotherapy arm.

      In a randomized phase II trial Gomez included 49 patients with stage IV NSCLC with three or fewer metastases, and no progression after first-line systemic therapy. The trial investigated LCT with stereotactic or conventionally fractionated radiotherapy or surgery versus maintenance therapy or observation. Patients in the LCT arm experienced improved PFS as well as improved OS [5].The trial was closed early because of a significant PFS and OS benefit in the LCT arm. With a median follow-up time of 38.8 months the PFS benefit with additional local therapy was 14.2 months versus 4.4 months in the maintenance therapy/observation arm (p=0.022). They also reported an impressive OS benefit in the LCT arm: 41.2 months versus 17.0 months (p=0.017). This OS benefit was achieved despite the fact that 41% of the patients in the maintenance therapy/observation arm crossed over to the local consolidative therapy arm at the time of progression. No additional grade 3 or greater toxicities were observed. It is important to know that these studies were performed in the pre-immunotherapy era.

      In patients with metachronous OMD (controlled primary tumour and 1-5 oligometastatic lesions) the effect of LCT on survival, toxicity, and quality of life in 99 patients was recently reported in the SABR-COMET trial: a randomized, phase 2 trial [4]. Patients were randomly assigned (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus stereotactic or conventional radiotherapy to all metastatic lesions (SABR group). Median overall survival was 28 months in the control group versus 41 months in the SABR group (p=0.090).

      Several reasons could explain the benefit by adding LCT for OMD in these trials:

      1) LCT potentiates the effects of systemic therapy

      2) By reducing the residual tumor burden, LCT delays the growth of distant micrometastatic disease

      3) LCT reduced the amount of treatment-resistant lung cancer cells

      4) Necrosis caused by LCT allows the immune system to induce an immune-specific reaction that affects distant cancer cells

      Conclusion: The synergy of local consolidative therapies combined with systemic treatments in oligometastatic patients is currently one of the most exciting developments in lung cancer treatment.

      Ref:

      1. Kwint M et al. Outcome of radical local treatment of non-small cell lung cancer patients with synchronous oligometastases. Lung Cancer. 2017 Oct;112:134-139. doi: 10.1016/j.lungcan.2017.08.006.

      2. De Ruysscher D et al. Progression-Free-Survival and Overall Survival beyond 5 years of non-small cell lung cancer patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450). JTO 2018 doi: 10.1016/j.jtho.2018.07.098.

      3. Iyengar P et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018 Jan 11;4(1):e173501. doi:10.1001/jamaoncol.2017.3501. Epub 2018 Jan 11.

      4. Gomez D et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019 Jun 20;37(18):1558-1565. doi: 10.1200/JCO.19.00201. Epub 2019 May 8.

      5. Palma D et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.Lancet. 2019 May 18;393(10185):2051-2058. doi: 10.1016/S0140-6736(18)32487-5. Epub 2019 Apr 11

      6. Gu X et al. Cryoablation combined with molecular target therapy improves the curative effect in patients with advanced non-small cell lung cancer J Int Med Res. 2011;39(5):1736-43​

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      CS01.03 - Technical Reasons of Local Treatment Define the Limits of NSCLC OMD in Terms of Number of Metastases, Not a Fixed Number (Now Available) (ID 3146)

      11:00 - 12:30  |  Presenting Author(s): Marta Scorsetti

      • Abstract
      • Presentation
      • Slides

      Abstract

      Currently there is no consensus on the definition of oligometastatic disease in NSCLC, with 3 or 5 lesions historically considered as the upper limit [1]. A low number of metastases, indeed, is a good although not perfect surrogate of the biology behind the oligometastatic state. In real life practice, the number of metastatic lesions is often misleading, since it is possible to find patients with more than 5 metastases affected by a slowly progressing disease, potentially taking advantage from local treatments. On the contrary, patients affected by just one or two metastases can progress very rapidly with a dismal prognosis, despite the apparent low disease burden.

      Since the number of metastases is not a perfect indicator of oligometastatic state and biomarkers really able to identify this disease are lacking, there is a trend favoring the technical feasibility of local treatment over the number of metastases to treat. This approach has pros and cons. On one side, the idea of killing all visible cancer cells independently by their number is appealing and possibly with a positive impact on patient prognosis. On the other side, clinical data supporting such an aggressive local treatment have still a low level of evidence. Moreover, the definition of “technically feasible” is quite vague, particularly in the world of radiation oncology. Indeed, radiotherapy is strongly related to technological development. The innovations in this setting have dramatically increased the possible indications of radiotherapy, also for oligometastases. With state of the art radiotherapy, we are now able to treat virtually all sites in the body and it is becoming really difficult to define an upper limit to the number of lesions that can be treated. However, this is feasible only with advanced technologies, like image guided radiotherapy (IGRT), motion management (4D CT, gating, tracking, etc.), and heavy particles in particular clinical settings (retreatment for instance). This trend is creating a gap between Radiation Therapy Departments, since some treatments are becoming safely deliverable only in well selected Institutions with high expertise in this field.

      Despite all recent technological achievements, some clinical settings remain in which the risk-benefit ratio should be carefully weighted before delivering ablative dose to a metastatic patient. For instance, there are still uncertainties in the treatment of central lung lesions abutting on the main bronchus [2] or, changing scenario, the amount of remaining healthy liver is still limiting liver metastases treatment in some situations [3]. More importantly, the goal of local treatment of an oligometastatic patient should be to change the natural history of the tumor, independently from the number of metastases we are able to treat. Treating all the metastases, even though safely feasible, remains just a technical exercise if no impact on prognosis, quality of life or symptoms control is achievable. Oligometastatic disease has definitely a different biology, and every effort should be in the direction of identifying this biology [4]. Technologies have developed faster than our clinical and biological knowledge, and this should be kept in mind.

      In conclusion, the number of metastases remains a good clinical indication of oligometastatic state, but this number should not be an insuperable limit in clinical practice. Technical feasibility of local treatments (as radiotherapy) should be always carefully weighted accounting for risk-benefit ratio. Being able to treat any number of metastases should not be considered as a good reason for doing it indiscriminately. Physicians should always consider the clinical and biological reasons for a local ablative treatment in a metastatic patient, independently by technical issues.

      [1] Hong JC, Salama JK. The expanding role of stereotactic body radiation therapy in oligometastatic solid tumors: What do we know and where are we going? Cancer Treatment Reviews 52 (2017) 22–32

      [2] Videtic GM, Donington J, Giuliani M et al. Stereotactic body radiation therapy for early stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology (2017) 7, 295-301

      [3] Mondlane G, Ureba A, Gubanski M et al. Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases. Radiat Oncol. 2018 Oct 22;13(1):206. doi: 10.1186/s13014-018-1151-6

      [4] Correa RJ, Salama JK, Milano MT et al. Stereotactic Body Radiotherapy for Oligometastasis Opportunities for Biology to Guide Clinical Management. Cancer J. 2016 Jul-Aug;22(4):247-56.

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      CS01.04 - NSCLC OMD is Defined by a Fixed Maximum Number of Metastases, Not Technical Reasons of Local Treatment (Now Available) (ID 3147)

      11:00 - 12:30  |  Presenting Author(s): GAVIN Michael WRIGHT

      • Abstract
      • Presentation
      • Slides

      Abstract

      Other than a select group of patients with solitary brain metastases and cT1-2a N0 resectable primary cancers, the idea of aggressively ablating metastatic non-small cell lung cancer (NSCLC) has always been considered unconventional. The resectable solitary cerebral metastasis has traditionally yielded better results than any other M1b disease, and this has been put down to careful selection and perhaps a different biology in these rare cases. It wasn’t until the publication of a large individual patient data meta analysis in 20141 that more general treatment of OMD could be benchmarked and taken seriously enough to consider clinical trials. This confirmed that in select populations, long-term survival was achievable by surgical or radio-ablation of a small number of metastases. Only 1.9% of the series had more than 3 metastases and only 3% of the series had multi-organ disease. A main finding of multivariate analysis was that those with any nodal disease (effectively another metastatic site) did poorly.

      The definition of the oligometastatic disease state (OMD) has always been elusive. In principle, it is defined as M1a-c disease with low metastatic burden (usually up to three or five lesions) and limited organ involvement (usually up to two sites). It is considered an intermediate condition between truly localized disease and widely metastatic disease. The reporting bias of 1-3 metastases seen in so many published treatment series is tacit acknowledgement that OMD only encompasses three or fewer metastases, and probably to just a single organ. Our own IALSC TNM staging system recognizes this in our M1 sub-stages.

      Unlike oligo-metastatic colorectal carcinoma, sarcoma or renal cell carcinoma, which have reproducibly achieved long term survival after pulmonary metastasectomy (and/or hepatic metastasectomy) for several decades, the pace of disease and apparent inevitability of shortened lifespan in a patient with metastatic NSCLC has led to self-regulation of this practice for our tumour specialty. The relatively poorer average cardio-pulmonary fitness of patients with lung cancer and the maxim of ‘first do no harm’ largely tempered any enthusiasm.

      As surgery has become increasingly less invasive/morbid, and therapies such as stereotactic ablative body radiotherapy (SABR) and radiofrequency ablation have become more readily available, the temptation is to expand indications for intervention well beyond their evidence base and/or cost-benefit ratio. The last 5 years has seen a proliferation of publications of eyebrow-raising SABR series outside of any clinical trial protocols. This is a slippery slope that surgeons have been accused of sliding down in pulmonary metastasectomy for colorectal carcinoma2. We must not let our enhanced ability to inflict therapy dictate whether or not a condition is appropriate to treat. The definition of OMD cannot be stretched arbitrarily to match our technological capabilities or we will waste huge resources and inevitably cause some harm by way of futile overtreatment.

      The ‘breakthrough’ SABR-COMET trial3 has invigorated discussion and enthusiasm for treating NSCLC oligometastatic disease on the basis that overall survival was superior with ablation of OMD (41 months) compared to the control group treated with palliative measures (28 months). This enthusiasm does need to be tempered by a few salient observations. Firstly, this was a phase 2 trial of mixed histologies with 66 recruits in the treatment arm and 33 in the control arm. In all, only 18 enrolled patients had NSCLC, with 12 in the treatment arm. It is indeterminate from the paper how well these particular NSCLC patients performed and the confidence intervals would be wide. The follow-up tail becomes decidedly ‘bushy’ after 1 year due to censorship. There were three treatment-related deaths and four other serious adverse effects not seen in the control arm. The control rate was less optimistic than in Rusthoven’s phase 1 trial4, with 75% having no progression in targeted lesions (compared to 49% in the control arm).

      The most telling information supporting the ≤3 metastasis OMD hypothesis is the number of metastases and number of organs involved in the recruited SABR-COMET patients. Only 7 recruits had more than 3 metastases, with 5 of these receiving SABR. It is not clear if ANY of these had NSCLC, but these are not dissimilar numbers to the aforementioned NSCLC meta analysis1.

      Historically, there is far more data on survival after metastasectomy for series excluding NSCLC. Only 1% of pulmonary metastasectomies in the International Registry of Lung Metastases5 had NSCLC and some may have been second primaries. Whilst 26% of cases had ≥4 metastases resected, this was largely confined to sarcoma and germ cell tumours, where aggressive resection and re-resection is considered standard of care. Their survival was still inferior to patients with either solitary or 2-3 metastases. This is despite the likelihood that patients with ≥4 metastases are “hyper-selected’, based on survival characteristics such as performance status, younger age, excellent fitness, anatomical location and favourable observed tumour behaviour. This creates a false impression that this group is receiving not dissimilar survival benefit as the cohort with ablation of 1-3 metastases.

      OMD as a hypothesis is very reasonable and deserves to be tested. Diluting the potential benefits by expanding that definition to match our technological wizardry is not. Clinical trial resources would be better mobilized to further study surgical and/or SABR metastasectomy in lung cancer with ≤3 metastases in a single organ before expanding umbrella trials to ≥4 metastases.

      References

      1. Ashworth, A. B. et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non–small-cell lung cancer. Clin Lung Cancer 15, 346–355 (2014).

      2. Treasure, T., Internullo, E. & Utley, M. Resection of pulmonary metastases: a growth industry. Cancer Imaging 8, 121–124 (2008).

      3. Palma, D. A. et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial. BMC Cancer 12, 8 (2012).

      4. Rusthoven, K. E. et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J. Clin. Oncol. 27, 1579–1584 (2009).

      5. Pastorino, U. et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The Journal of Thoracic and Cardiovascular Surgery 113, 37–49 (1997).

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Author of

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    EP1.18 - Treatment of Locoregional Disease - NSCLC (ID 208)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.18-16 - Surgery for Locally Advanced Lung Cancer Invading the Spine After Chemoradiotherapy (Now Available) (ID 2371)

      08:00 - 18:00  |  Author(s): Tomoyuki Hishida

      • Abstract
      • Slides

      Background

      Treatment for locally-advanced lung cancer invading the spine remains challenging, and multimodality treatment should be considered. The aim of this study was to clarify surgical outcomes following induction chemoradiotherapy (CRT) for lung cancer invading the spine following chemoradiotherapy.

      Method

      We retrospectively reviewed clinical and pathological data of locally-advanced lung cancer patients with vertebral invasion, in who we have performed total or partial vertebrectomy after induction CRT between 2011 and 2017.

      Result

      A total of 4 patients were extracted. All patients were diagnosed as cT4N0M0 disease based on chest computed tomography (CT) and positron emission tomography (PET)-CT, and vertebral invasion was evaluated by chest computed tomography (CT) and magnetic resonance imaging. The histologic type included adenocarcinoma in 3 patients and squamous cell carcinoma in one patient, respectively. Average dose of radiation was 50 Gy. Total vertebrectomy was performed in 3 patients and transverse-process resection in one patient. Average Median operation time and blood loss were 800 minutes and 878 ml, respectively. In all 4 cases, complete R0 resection was performed. There was no perioperative and in-hospital death, and complication occurred in one patient. Median follow-up period was 39 months (range, 16-63 months), and median overall survival time and relapse free survival time were 39 months (range, 16-63 months) and 29months (range, 7-63 months).

      Conclusion

      The current preliminary result indicated that lung cancer surgery combined with vertebrectomy after induction CRT was feasible. Although our series were small, this multimodal treatment strategy might be a option for cT4N0M0 lung cancer invading to the spine. Further study should be conducted to confirm the current result with a large sample size.

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    MA01 - Oligometastatic Disease (ID 114)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
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      MA01.12 - Discussant - MA01.09, MA01.10, MA01.11 (Now Available) (ID 3717)

      10:30 - 12:00  |  Presenting Author(s): Tomoyuki Hishida

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-04 - Multicenter Observational Study of Node-Negative Non-Small Cell Lung Cancer Patients Who Are Excluded from a Clinical Trial (ID 678)

      09:45 - 18:00  |  Author(s): Tomoyuki Hishida

      • Abstract

      Background

      The Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial (JCOG0707), which compared the survival benefit of tegafur/uracil (UFT) and tegafur/gimeracil/oteracil (S-1) for completely resected pathological stage I (T1>2 cm and T2 in the 6th TNM classification) non-small cell lung cancer (NSCLC). A total of 963 patients were enrolled. Recently, there is a growing concern that those who participated in clinical trials are highly selected and do not represent the “real-world” population. Hereby, we conducted a multicenter observational study of patients excluded from JCOG0707 trial during the study period.

      Method

      Patients with completely resected pathological stage I NSCLC, eligible for, but excluded from the JCOG0707 trial during the enrollment period (Nov. 2008– Dec. 2013) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. The final survival data were collected as of Dec. 2018.

      Result

      Of the 48 institutions participating in JCOG0707, 34 participated in this observational study. They had enrolled 917 (“JCOG” cohort) to JCOG0707. To this study, 5004 patients (“All” cohort), or 85% of those initially considered for JCOG0707 at the 34 institutions, were enrolled. Among them, 2388 (47.7%) were ineligible for the trial and 2616 (52.3%) had not been enrolled to JCOG0707 despite being eligible (“Eligible” cohort). Of the 5004 patients, 1659 (33.2%) received adjuvant chemotherapy, mainly UFT (1550 of 1659, or 93.4% of those received any adjuvant chemotherapy).

      The 5-year survival rates (5yOS) for All and Eligible cohorts were 83.9% and 89.1%, respectively, versus 89.2% in the JCOG cohort. The 5yOS with UFT adjuvant were 89.4% in Eligible and 88.9% in JCOG cohorts, respectively.

      UFT administration was a significant prognostic factor in All (adjusted HR=0.66, p<0.0001), but not in Eligible cohort (adjusted HR=0.88, p=0.28). The patients were classified into 3 subgroups, those with tumors without GGA (ground-glass area, non-invasive component; GGA-), with GGA (GGA+) and tumor size < 3 cm, and GGA+ with tumor size > 3cm. 5yOS of 744 patients in the Eligible cohort with GGA+ and tumor size < 3cm were excellent, 96.9%/96.4% with/without UFT. For 416 patients with GGA+ tumor sized > 3cm in Eligible cohort, invasive tumor size in the pathological specimen was prognostic but not predictive for UFT effect. When the invasive tumor size was >3 cm, 5yOS with/without UFT were 90.0/87.8%, whereas when it was <3 cm, 5yOS with/without UFT were 96.2/96.2%. UFT tended to be associated with better prognosis in 1389 patients with GGA- tumor when the tumor size was >3 cm, (5yOS 83.8% vs 77.4%, adjusted HR=0.82, p=0.27), but not when it was <3 cm (5yOS 88.1% vs 88.1%, adjusted HR=0.97, p=0.87).

      Conclusion

      Our “real-world” data reproduced the survival outcome of JCOG0707, especially in Eligible cohort. Invasive tumor size was a prognostic factor in GGA+ tumors, suggesting validity of the 8th IASLC TNM classification. GGA+ tumor with invasive tumor size of <3 cm would not require any adjuvant therapy. UFT effect appears to be limited to large GGA- tumor.

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    WS05 - Staging Workshop Part 2: The Importance of Invasive Nodal Staging in Thoracic Malignancies (ID 106)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Staging
    • Presentations: 1
    • Now Available
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      WS05.03 - How to Perform a Proper Systematic Nodal Dissection in Lung Cancer Surgery (Now Available) (ID 3686)

      15:45 - 17:15  |  Author(s): Tomoyuki Hishida

      • Abstract
      • Presentation
      • Slides

      Abstract

      In 1960, Cahan first reported lobectomy with regional lymph node dissection, which was called “radical lobectomy.”1 Since then, this procedure has been widely accepted, and systematic nodal dissection (SND) is an internationally accepted standard procedure for lymph node dissection in cases of non-small cell lung cancer (NSCLC). The purpose of SND is aimed at removal of all mediastinal lymph node stations regardless of the anatomical location of the primary tumor in the lobe. The significance of SND can be discussed from the clinical aspects of accurate staging and survival benefit. Metastatic lymph nodes obtained via SND can undergo careful and accurate accurate histopathological evaluation, which offers several clinical advantages. However, the therapeutic effect of SND remains unclear.2-5

      Technically, SND involves complete excision of all tissues in a particular anatomical compartment along with a few components of surrounding anatomical structures. An ideal technique involves en bloc removal of all tissue that may contain cancer cells, including lymph nodes and surrounding fatty tissue within pre-defined anatomical landmarks. All of lobectomies for NSCLC are performed via posterolateral incision using minimally invasive open surgery (MIOS) approach in our institution. Common to both sides, the fourth or fifth intercostal space provides better access in SND. During the SND, special care is warranted to prevent interruption of the lymphatic vessels and/or injury to the lymph nodes themselves. Additionally, connective tissue ligation is necessary in a few cases to prevent postoperative chylothorax. Identification of the bilateral recurrent nerves is important because recurrent nerve paralysis can cause serious postoperative complications. Based on AOSOG Z0030 trial, complications of SND include postoperative chylothorax (1.7%), intraoperative bleeding (1.1%), and recurrent laryngeal nerve injury (0.9%).5

      Although SND is a standard procedure of lymph node dissection for NSCLC, previous studies have analyzed in detail the lymphatic pathway and the pattern of lymph node involvement based on the primary location by lobe. Asamura et al. 6 reported that right upper lobe tumors and left upper segment tumors tend to metastasize to the superior mediastinum and that these lesions rarely metastasize to the subcarinal nodes without concomitant metastasis to the hilar or superior mediastinal nodes.6 The lobe-specific patterns of nodal metastases are being recognized owing to increasing analyses of the lymph node metastatic pathway.6-9 Based on these results, lobe-specific lymph node dissection is being increasingly performed under certain conditions, for example, based on tumor location, tumor size, cell type, and the percentage of the area of ground glass opacity visualized in the tumor on computed tomography.

      References

      1. Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg; 1960;39:555-572.
      2. Izbicki JR, Passlick B, Pantel K, et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non small cell lung cancer. Ann Surg 1998;227:138-144.
      3. Sugi K, Nawata K, Fujita N, et al. Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg 1998;22:290-294.
      4. Wu Y, Huang ZF, Wang SY, et al. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer 2002;36:1- 6.
      5. Wright G, Manser RL, Byrnes G, et al. Surgery for non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials. Thorax 2006;61:597-603.
      6. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas based on a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg 1999; 117:1102-1111
      7. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lymph node involvement, recurrence, and prognosis in resected small, peripheral non-small cell carcinoma of the lung. Are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996;111:1125-1134
      8. Okada M, Tsubota N, Yoshimura M, et al. Prognosis of completely resected pN2 non-small cell carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg 1999;118:270-275
      9. Watanabe S, Suzuki K, Asamura H. Superior and basal segment lung cancers in the lower lobe have different lymph node metastatic pathways and prognosis. Ann Thorac Surg 2008;85:1026-1031.

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