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José Belderbos
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CS01 - Controversies in NSCLC OMD (ID 3)
- Event: WCLC 2019
- Type: Controversy Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:Tomoyuki Hishida, Yolande Lievens
- Coordinates: 9/09/2019, 11:00 - 12:30, Colorado Springs (1994)
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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
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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MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Simon Ekman, Helena A Yu
- Coordinates: 9/08/2019, 15:15 - 16:45, Tokyo (1982)
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MA08.07 - The Concordance Between Patient Reported Outcomes and Clinician Reported Outcomes During Radiotherapy in Lung Cancer Patients (Now Available) (ID 2507)
15:15 - 16:45 | Author(s): José Belderbos
- Abstract
- Presentation
Background
Capturing information on toxicity in (non-)small cell lung cancer patients receiving radiotherapy or chemoradiotherapy, is crucial for optimal symptom management. Patient Reported Outcomes (PROs) have the potential to improve toxicity detection by adding direct information from the patient perspective. The aim of this study is therefore to determine the predictive and additional value of PROs on prospectively scored clinician reported toxicity.
Method
An observational study was performed in lung cancer patients (n=111) treated with (chemo)radiation with curative intent. The EORTC QLQ-C30 and the EORTC LC-13 questionnaires were used to score PROs on a scale of 0-100 for a selection of commonly occurring toxicities (i.e. dysphagia, dyspnea, anorexia, fatigue, cough and nausea). Clinicians prospectively scored the maximum toxicity during, and at the end of treatment using the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance (i.e. discrimination) of PROs on predicting clinician scored CTCAE toxicity (grade ≥2). Furthermore, cut-off points were determined from the ROC-curve on the basis of the best trade‐off values between sensitivity and specificity (0,5). Validity of the model was assessed with the ability to predict the number of grade ≥2 toxicities (calibration).
Result
Assessment of predictive performance in our cohort demonstrated a good fit for anorexia (AUC: 0,810 95% CI 0,699 to 0,921) and dysphagia (AUC: 0,828 95% CI 0,743 to 0,914) with sensitivity scores of 85,7%, 67,4% and specificity scores of 74,0% and 92,6% respectively. Both dyspnoea (AUC: 0,765 95% CI 0,60 to 0,910) and nausea (AUC: 0,745, 95% CI 0,548 to 0,942) showed a fair fit with sensitivity score of 74,1% for both toxicities and specificity of 69,1% and 68,3% respectively. A poor fit was found for cough (AUC: 0,667 95% CI 0,495-0,839) with a sensitivity of 55,6% and specificity of 30,4%. The model failed to discriminate for fatigue (AUC: 0,507 95% CI 0,368-0,645). Calibration showed that clinician based CTCAE toxicities substantially underestimated all PRO-based toxicities.
Conclusion
This study has identified that patient reported toxicities and clinician reported toxicities do not always concord. Only anorexia and dysphagia showed good agreement, while for the other toxicities, the agreement was only fair to poor. Furthermore, we showed that clinicians substancially underreport the existence of toxicities. This study adds to the growing body of evidence indicating the potential beneficial role of using PRO-based toxicity reporting in clinical cancer care for lung cancer.
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OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Dirk De Ruysscher, Bartomeu Massuti
- Coordinates: 9/09/2019, 15:45 - 17:15, Seoul (2007)
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OA12.08 - Discussant - OA12.05, OA12.06, OA12.07 (Now Available) (ID 3790)
15:45 - 17:15 | Presenting Author(s): José Belderbos
- Abstract
- Presentation
Abstract not provided
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-115 - Long-Term Effects of Concurrent Chemoradiotherapy on Quality of Life in Locally Advanced Non-Small Cell Lung Cancer Patients (ID 1780)
09:45 - 18:00 | Author(s): José Belderbos
- Abstract
Background
Concurrent chemoradiotherapy imposes beneficial effects on overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC). Currently, it is unknown what the effects on long-term health-related quality of life (HRQOL) are. Therefore, we investigated long-term HRQOL in locally advanced NSCLC patients treated with concurrent chemoradiotherapy, using an accelerated fractionation scheme of 24 x 2.75 Gy +/- Cetuximab.
Method
A 2-armed phase II, multi-center study (NTR2230) was performed with the initial aim to assess the effect of additional Cetuximab to concurrent chemoradiotherapy in locally advanced NSCLC patients. Arm A received high dose accelerated radiotherapy (24 x 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m2). Arm B additionally received weekly Cetuximab (400 mg/m2 one-week pre-treatment followed by weekly 250 mg/m2). HRQOL was assessed using the EORTC QLQ-C30 at baseline, 3 months post treatment and after 1 year. The primary endpoints included dyspnea, pain, physical functioning, cognitive functioning and the QLQ-C30 summary score. Following the EORTC guidelines, the scores of the endpoints were linearly transformed to 0–100 scales. Higher scores correspond to improved functioning for the functioning scales and for the summary score while for symptom scales (pain and dyspnea), higher scores indicate more symptoms. Linear mixed-modeling was used to assess differences over time. Standardized effect sizes based on the t-test statistic were calculated: (2*t)/(√degrees of freedom). Effect sizes of 0.2 were considered small, 0.5 moderate and clinically relevant, and 0.8 large.
Result
Between February 2009 and May 2011, 102 patients were randomly allocated in two arms; 51 patients (50%) in arm A and 51 patients (50%) in arm B. Of those, 79 (77%) patients had at least one evaluable questionnaire. Figure 1 shows the development of the HRQOL endpoints over time. Over time, physical functioning (ES 0.48, P-value 0.003), cognitive functioning (ES 0.37, P-value 0.020), dyspnea complaints (ES 0.67, P-value <0.001) and the summary score (ES 0.44, P-value 0.006) significantly worsened. Only pain showed a reversing pattern in which pain was less present at 1 year (ES 0.37, P-value 0.021). No differences between the two arms were found.
Conclusion
In this randomized study of locally advanced NSCLC patients treated with concurrent chemoradiotherapy with or without Cetuximab, a clinically meaningful and long-term decline for all HRQOL endpoints except pain was observed. This analysis suggests that although concurrent chemoradiotherapy improves OS in NSCLC patients, efforts should also be taken to improve long-term HRQOL.
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P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.18-18 - Feasibility of Hypofractionated Chemoradiation for Patients with Stage III Non-Small Cell Lung Cancer (Now Available) (ID 2598)
09:45 - 18:00 | Author(s): José Belderbos
- Abstract
Background
The standard treatment for fit patients with stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation often consisting of a platinum doublet and 60-66Gy. In the Netherlands an alternative is mildly hypofractionated radiotherapie (66Gy in 24 fractions of 2.75 Gy) combined with daily low dose Cisplatinum. This schedule aims to improve local tumor controle and overall survival by reducing overall treatment time. We investigated the feasibility of three weekly full dose platinum doublet chemotherapy combined with hypofractionated radiotherapy. The rational for full dose platinum doublet chemotherapy is to reduce the incidence of distant metastases.
Method
A retrospective observational study was performed including patients with stage III NSCLC (<70 years old, WHO performance score 0-1, estimated length of the oesophagus receiving 66Gy ≤12cm) who were treated with full dose platinum doublet chemotherapy and 66Gy/24 fractions. All patients were staged with a PET-scan and brain MRI. Chemotherapy generally consisted of 1 cycle of Cisplatin/Alimta or Cisplatin/Gemcitabine followed by 2-3 cycles of Cisplatin/Etoposide. Radiotherapy mostly started on day two of the second cycle of chemotherapy. Patients with a single mediastinal lymphnode metastasis who were selected for surgery after chemoradiation are not included in this analysis. Toxicity was scored using the common criteria for adverse events (CTCAE v4.0): acute if it occurred ≤90 days, late >90 days.
Result
Between 2012-2019, 40 patients were treated with hypofractionated radiotherapy and platinum doublet chemotherapy. The median age was 58 years (SD 8.9), all had a WHO 0-1, and 58% were male. The median follow-up was 3.3 years (IQR 1.7 – 3.9). The median overall survival was 1.6 years (IQR 0.6-3.2). The rate of distant metastases was 30% at two years, and the median progression free survival was 0.9 years. Grade ≥3 acute oesophageal toxicity occurred in 14 patients (35%) and late oesophageal toxicity in 7 patients (17.5%). Five patients died: all due to oesophagus perforation or broncho-oesophageal fistula.
Conclusion
In selected fit patients with locally advanced stage III NSCLC hypofractionated radiotherapy with concurrent full dose Cisplatin based chemotherapy resulted in an unexpected high rate of severe acute and late esophageal toxicity.
