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CS01 - Controversies in NSCLC OMD (ID 3)
- Event: WCLC 2019
- Type: Controversy Session
- Track: Oligometastatic NSCLC
- Presentations: 4
- Now Available
- Moderators:Tomoyuki Hishida, Yolande Lievens
- Coordinates: 9/09/2019, 11:00 - 12:30, Colorado Springs (1994)
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
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.
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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
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.  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  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 .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 . 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.
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
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
Currently there is no consensus on the definition of oligometastatic disease in NSCLC, with 3 or 5 lesions historically considered as the upper limit . 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  or, changing scenario, the amount of remaining healthy liver is still limiting liver metastases treatment in some situations . 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 . 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.
 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
 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
 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
 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.
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
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.
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).
P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.16-40 - Real-World Neurocognitive Function in Lung Cancer: Initial Results of the PRO-Long Study (ID 2205)
09:45 - 18:00 | Author(s): Yolande Lievens
Changes in neuro-cognitive function (NCF) as a result of treatment and disease have been repeatedly reported in cancer patients. However, contradictions exist on the prevalence and extent of impairment. Evidence in the lung cancer population is very limited. We here report the initial results of NCF in non-small cell lung (NSCLC) cancer patients receiving radiotherapy and/or systemic therapy in the PRO-Long study.Method
PRO-Long is a monocentric, prospective, longitudinal study, investigating the effect of first-line chemotherapy, radiotherapy and/or immunotherapy on patient-reported health-related quality of life (HRQoL), toxicity, functional exercise capacity (6-minute walking test – 6MWT) and NCF in locally-advanced and metastatic NSCLC patients. HRQoL and toxicity data are collected with patient-reported outcome measurements (PROMs). NCF data is collected with the Reys-Osterrieth Complex Figure Test (ROCF), Hopkins Verbal Learning Test-Revidsed (HVLT-R) free recall, delayed recall and recognition; Trail Making Test (TMT) A and B, Controlled Oral Word Association Test (COWA), Wechsler Adult Intelligence Scale (WAIS) digit span and the Stroop Color and Word Test (SCWT).
Demographic data are collected at baseline; outcome data (survival, local and loco-regional control and metastatic relapse) during follow-up. NCF data is collected pre-treatment, and 2-3 months, 6 and 12 months after the end of treatment in patients receiving chemo- and/or radiotherapy or after start of immunotherapy. The mixed model approach was applied to determine statistical significance (p < 0.05). Meaningful clinical important difference (MCID) in NCF is defined as a decline greater than one standard deviation from baseline.Result
Between January 2016 and December 2018, 50 patients (mean age: 63) were recruited. The majority was male (60%), had locally-advanced disease (54%) and received chemotherapy with (50%) or without (24%) radiotherapy. NCF data is available of 49, 28, 16 and 10 patients at baseline, 2-3 months, 6 months and 1 year respectively. So far no significant decline was found in any NCF test.
At 2-3 and 6 months after treatment, 42% and 34% of patients had a MCID decline in one or more tests. NCF decline was mostly detected in the HVLT-R free recall test, respectively 15 and 23% at 2-3 and 6 months.Conclusion
The initial data suggest that systemic treatment, all or not combined with radiotherapy may result in a clinically meaningful NCF decline in locally-advanced and metastatic NSCLC patients. Particularly, immediate recall seems to be affected. Updated results will be presented.