Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Demographic and Baseline Clinical Data
2.2. Treatment of BM
2.3. Driver Mutation Status
2.4. Clinical Status
2.5. Survival Outcome
3. Discussion
4. Patients and Methods
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ALK | anaplastic lymphoma kinase |
BM | brain metastasis |
BRAF | v-raf murine sarcoma viral oncogene homolog B1 |
CT | computer tomography |
EGFR | epidermal growth factor recetor |
ErbB2 | Erb-B2 Receptor Tyrosine Kinase 2 |
FGFR | fibroblast growth factor receptor |
HR | Hazard ratio |
KPS | Karnofsky performance scale |
KRAS | Kirsten rat sarcoma viral oncogene |
LINAC | linear accelerator |
MET | Mesenchymal–epithelial transition |
(c)MRI | (cranial)magnetic resonance imaging |
N/A | not applicable |
NSCLC | non-small cell lung cancers |
OS | overall survival |
PIK3CA | Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha |
ROS | (reactive oxygen species |
RPA | recursive partitioning analysis |
RTOG | Radiation Therapy Oncology Group |
SRS | stereotactic radiosurgery |
WBRT | whole brain radiation therapy |
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Parameter | Precocious (n = 99) | Synchronous (n = 152) | Metachronous (n = 126) | All (n = 377) | p-Value |
---|---|---|---|---|---|
Age [median; range] | 62 (38–87) | 62 (32–85) | 60 (25–83) | 61 (25–87) | 0.76 |
Male gender [n;%] | 56 (56.6) | 88 (57.9) | 63 (50.0) | 207 (54.9) | 0.26 |
Controlled primary disease [n;(%)] | 0 (0) | 37 (24.3) | 57 (45.2) | 94 (24.9) | <0.0001 |
Histology [n;%] | 0.10 | ||||
Adeno | 78 (78.8) | 127 (83.5) | 104 (82.5) | 309 (82.0) | |
Squamous cell | 14 (14.1) | 13 (8.6) | 19 (15.1) | 46 (12.2) | |
Neuro-endocrine | 0 (0) | 3 (2.0) | 2 (1.6) | 5 (1.3) | |
NOS | 7 (7.1) | 9 (5.9) | 1 (0.8) | 17 (4.5) | |
Previous treatment for primary disease | <0.0001 | ||||
none | 99 (100) | 16 (10.5) | 4 (3.2) | 119 | |
Surgery | 0 (0) | 27 (17.8) | 68 (54.0) | 95 | |
Neo-adjuvant Chemotherapy | 0 (0) | 14 (9.2) | 20 (15.9) | 34 | |
Neo-adjuvant radiotherapy | 0 (0) | 0 (0) | 12 (9.5) | 12 | |
Chemotherapy | 0 (0) | 63 (41.4) | 89 (70.6) | 152 | |
Radiotherapy | 0 (0) | 21 (13.8) | 47 (37.3) | 68 | |
Molecular treatment | 0 (0) | 6 (3.9) | 26 (20.6) | 32 | |
Unknown | 0 (0) | 5 (3.3) | 5 (4.0) | 10 | |
BM count [n;%] | 0.11 | ||||
1 BM | 60 (60.6) | 80 (52.6) | 59 (46.8) | 199 (52.8) | |
2–3 BM | 29 (29.3) | 51 (33.6) | 38 (30.2) | 118 (31.3) | |
≥4 BM | 10 (10.1) | 30 (19.8) | 29 (23.0) | 69 (18.3) | |
Mutational status [n;%] | 0.002 | ||||
N/A | 29 (29.3) | 79 (52.0) | 34 (27.0) | 142 (37.7) | |
Wild type | 36 (36.4) | 18 (11.8) | 40 (31.7) | 94 (24.9) | |
EGFR | 4 (4.0) | 28 (18.4) | 19 (15.1) | 51 (13.6) | |
KRAS | 7 (17.2) | 20 (13.2) | 21(16.7) | 58 (15.4) | |
MET | 6 (6.1) | 3 (2.0) | 4 (3.2) | 13 (3.4) | |
BRAF | 1 (1.0) | 0 (0) | 1 (0.8) | 2 (0.5) | |
ALK | 1 (1.0) | 1 (0.7) | 1 (0.8) | 3 (0.8) | |
ROS | 0 (0) | 0 (0) | 3 (2.4) | 3 (0.8) | |
FGFR | 2 (2.0) | 1 (0.7) | 1 (0.8) | 4 (1.1) | |
PIK3CA | 0 (0) | 2 (1.3) | 0 (0) | 2 (0.5) | |
ErbB2 | 3 (3.0) | 0 (0) | 2 (1.6) | 5 (1.3) | |
Tumor location [n;(%)] | 0.17 | ||||
Supratentorial | 46 (46.5) | 86 (56.6) | 64 (50.8) | 196 (52.0) | |
Infratentorial | 22 (22.2) | 25 (16.4) | 11 (8.7) | 58 (15.4) | |
Supra- and infratentorial | 31 (31.3) | 41 (27.0) | 51 (40.5) | 123 (32.6) | |
Symptomatic BM [n;(%)] | <0.0001 | ||||
Neurological deficits [n] | 97 (98.0) | 90 (59.2) | 71 (56.3) | 258 (68.4) | |
Seizures | 15 | 21 | 12 | 48 | |
Aphasia | 14 | 11 | 8 | 33 | |
Hemiparesis | 26 | 28 | 21 | 75 | |
Visual field defects | 1 | 13 | 5 | 19 | |
Cerebellar signs | 39 | 10 | 20 | 69 | |
Signs of elevated intracranial pressure | 30 | 26 | 18 | 74 | |
KPS at presentation [median; range] | 80 (40–100) | 90 (40–100) | 90 (50–100) | 80 (40–100) | 0.03 |
RPA class prior to BM treatment | <0.0001 | ||||
Class I | 0 | 0 | 34 | 34 | |
Class II | 79 | 133 | 72 | 284 | |
Class III | 20 | 19 | 20 | 59 | |
RPA class after BM treatment | <0.0001 | ||||
Class I | 0 | 1 | 34 | 35 | |
Class II | 97 | 139 | 78 | 314 | |
Class III | 2 | 12 | 14 | 28 | |
Treatment modality | <0.0001 | ||||
Surgery + postoperative radiotherapy | 84 (84.8) | 91 (59.9) | 70 (55.6) | 245 (65.0) | |
Stereotactic radiosurgery | 15 (15.2) | 61 (40.1) | 56 (44.4) | 132 (35.0) | |
Systemic medical treatment after BM | 0.09 | ||||
Treatment modality (n = 238) | 68 (68.7) | 102 (67.1) | 71 (56.3) | 241 (63.9) | |
Chemotherapy | 42 | 72 | 57 | 171 | |
Molecular therapy | 39 | 39 | 24 | 102 | |
Dead by time of analysis | 62 (62.6) | 103 (67.8) | 67 (53.2) | 232 (61.5) | |
Cause of death | <0.0001 | ||||
Unknown | 8 (12.9) | 67 (65.0) | 23 (34.3) | 101 (43.5) | |
Neurological | 4 (6.5) | 7 (6.8) | 10 (14.9) | 21(9.1) | |
Systemic disease progression | 46 (74.1) | 26 (25.2) | 34 (50.7) | 106 (45.7) | |
others | 4 (6.5) | 3 (2.9) | 6 (9.0) | 13 (5.6) |
Parameter | Univariate (Log Rank) [p-Value] | Multivariate (Cox Regression) [HR 95%CI; p-Value] |
---|---|---|
Age ≤ 65 | 0.88 | |
Controlled systemic status | 0.15 | |
Timing | 0.76 | |
Precocious vs. synchronous | 0.71 | |
Precocious vs. metachronous | 0.82 | |
Synchronous vs. metachronous | 0.33 | |
KPS ≥ 70 post-BM-treatment | <0.0001 | 0.38, 0.28–0.58, p < 0.0001 |
BM count | ||
Single vs. oligo vs. multi | 0.99 | |
Systemic treatment after BM | <0.0001 | 0.48, 0.39–0.63, p < 0.0001 |
Radiosurgery only | 0.002 | n.s. |
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Jünger, S.T.; Schödel, P.; Ruess, D.; Ruge, M.; Brand, J.-S.; Wittersheim, M.; Eich, M.-L.; Schmidt, N.-O.; Goldbrunner, R.; Grau, S.; et al. Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments. Cancers 2020, 12, 3618. https://doi.org/10.3390/cancers12123618
Jünger ST, Schödel P, Ruess D, Ruge M, Brand J-S, Wittersheim M, Eich M-L, Schmidt N-O, Goldbrunner R, Grau S, et al. Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments. Cancers. 2020; 12(12):3618. https://doi.org/10.3390/cancers12123618
Chicago/Turabian StyleJünger, Stephanie T., Petra Schödel, Daniel Ruess, Maximilian Ruge, Julia-Sarita Brand, Maike Wittersheim, Marie-Lisa Eich, Nils-Ole Schmidt, Roland Goldbrunner, Stefan Grau, and et al. 2020. "Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments" Cancers 12, no. 12: 3618. https://doi.org/10.3390/cancers12123618