Demographic features and clinical findings
A summary of demographic and clinical characteristics of eligible patients is displayed in Table 1. Eligible patients were predominately Caucasian (84%), with a median age at LMC diagnosis of 55.7 years (range- 25.0–84.9 years). The most common sites of primary tumor were breast, lung, and melanoma (43%, 26%, and 10%, respectively). Tumors associated with LMC were characterized by high grade histology (3% grade 1, 18% grade 2, and 46% grade 3), advanced stage disease at presentation (Stage I 7%, Stage II 17%, Stage III 25%, and Stage IV 46%), and nodal involvement (71%). In patients with metastases prior to LMC diagnosis, the most common sites were bone (36%), brain (33%), and lung (12%). The baseline ECOG performance status at the time diagnosis of LMC was ≤ 1 in 61% ≥ 2 in 35% of patients.
Table 1
| Total (n = 153) |
Age at LMC Diagnosis Median [IQR] | 55.7 years [48, 62.5] |
Race White Black Other | 128 (84%) 16 (10%) 9 (6%) |
Site of primary cancer diagnosis | |
Breast | 66 (43%) |
Lung | 40 (26%) |
Melanoma | 16 (10%) |
Head/Neck | 8 (5%) |
Renal | 2 (1%) |
Ovarian | 3 (2%) |
Prostate | 4 (3%) |
Other | 14 (9%) |
Initial stage at diagnosis | |
I | 10 (7%) |
II | 26 (17%) |
III | 38 (25%) |
IV | 71 (46%) |
Unknown | 8 (5%) |
Histologic Grade | |
I | 4 (3%) |
II | 28 (18%) |
III | 71 (46%) |
Unknown | 50 (33%) |
Biomarker status for Breast Primary (n = 66) | |
Estrogen Receptor | |
Negative | 24 (16%) |
Positive | 40 (26%) |
Unknown | 2 (1%) |
Progesterone Receptor | |
Negative | 30 (20%) |
Positive | 30 (20%) |
Unknown | 3 (2%) |
HER2 Status | |
Negative | 45 (29%) |
Equivocal | 2 (1%) |
Positive | 18 (12%) |
Unknown | 3 (2%) |
Nodal Involvement | |
Yes | 109 (71%) |
No | 36 (24%) |
Unknown | 8 (5%) |
ECOG Performance Status | |
0 | 31 (20%) |
1 | 62 (41%) |
2 | 33 (22%) |
3 | 17 (11%) |
4 | 3 (2%) |
Unknown | 7 (5%) |
Site of first Metastasis | |
Bone | 55 (36%) |
Brain | 51 (33%) |
Lung | 18 (12%) |
Liver | 8 (5%) |
Spinal Cord | 1 (1%) |
Other | 17 (11%) |
None | 2 (1%) |
Missing | 1 (1%) |
Outcomes
Among this cohort, there were 150 (98%) observed deaths. The median OS was 1.9 months (95% CI: 1.3, 2.5). The median time from primary cancer diagnosis to development of LMC was 2 years (IQR: 1-5.4 years). The median time from initial metastatic disease to development of LMC was 0.5 years (IQR: 0-1.9 years) overall and was similar among primary cancer subtypes. Breast cancer was associated with the longest interval from metastasis to LMC of 0.7 years (IQR 0.0-2.4 years), and lung cancer was associated with the shortest interval of 0.5 years (IQR 0.0-0.8 years).
Differences were noted in the Kaplan-Meier estimates for OS between primary cancer diagnoses. The median OS in primary breast cancer was 2.4 months (95% CI: 1.2, 4.4), primary lung cancer was 1.3 months (95% CI: 0.9, 2.1), primary melanoma was 1.7 months (95% CI: 0.8, 3.5), and other primary cancers was 2.6 months (95% CI: 0.7, 3.5) (ANOVA p = 0.012) (Fig. 1). There was no difference detected in OS between ECOG performance status groups with a median OS of 2.0 months (95% CI: 1.5, 2.8) for patients with ECOG performance status 0–2 and 0.7 months (95% CI: 0.5, 3.2) for those with ECOG performance status 3 or 4 (p = 0.255) (Fig. 2).
Diagnostic Findings
MRI of the brain and/or spine was performed in all patients (100%), and of those, 97% of patients had radiographic evidence of LMC. Of the 67 patients who underwent LP, CSF cytology was positive in 22%, equivocal in 7%, and negative in 16%. As depicted in Fig. 3, the Kaplan-Meier curves revealed differences in OS by CSF cytology: median OS for CSF negative patients was 3.8 months (95% CI: 2.1, 9.8), for CSF equivocal was 2.4 months (95% CI: 0.5, 11.0), and for CSF positive patients was 0.9 months (95% CI: 0.5, 1.3) (p < 0.005).
Management Of Therapeutic Strategy
Of the 153 patients, 24 (16%) had no new treatment after LMC diagnosis and 129 (84%) had a new addition of radiation to the brain or spine, addition of intrathecal chemotherapy, or a new systemic chemotherapy agent. The most common addition was radiotherapy in 30 patients (42%). The most likely new agent was the addition of capecitabine in 6 patients (8%). Twenty-eight (18%) patients received intrathecal chemotherapy with 27 (96%) receiving liposomal cytarabine and 1 (4%) receiving thiotepa. The median OS for patients with no new treatment after LMC diagnosis was 0.7 months (95% CI: 0.6, 1.2) and for those with a change in treatment after LMC diagnosis, 2.4 months (95% CI: 1.6, 3.1) (p < 0.001, Fig. 4).
Breast Cancer Subset Analysis
A separate analysis was performed specifically on the subset of patients with a primary breast cancer (see Table (1) for tumor characteristics). 37 breast cancer patients received radiotherapy for LMC (56%) and 64 received chemotherapy for either the primary disease or LMC (97%), with 22 patients (36%) receiving intrathecal chemotherapy and 42 patients (64%) receiving hormonal therapy.
Of the 66 patients, there were 64 (97%) observed deaths; and the survival differed for patient based on their biomarker status. Median OS for all patients was 2.4 months (95% CI: 1.2–4.4). Median OS for ER+/PR+/HER2- patients (n = 40, 61%) was 4.1 months (CI: 1.7, 9.8), for triple negative breast cancer (TNBC) patients (n = 17, 26%) was 0.9 months (CI: 0.2, 1.9) and for HER2 + patients (n = 6, 9%) was 0.7 months (CI: 0.0, 15.8). A significant difference in OS between subtypes based on hormone receptor status was found (p-0.002, log-rank test). OS was improved with new treatment after LMC diagnosis, with median OS of 2.8 months (CI: 1.3, 5.7) in treated patients (n = 57, 86%) compared to 1.2 months (CI: 0.03, 3.6) in untreated patients (n = 9, 14%) (p-0.026). The median OS in CSF negative patients was 15.3 months (CI: 3.6, 30.1), 6.9 months in CSF equivocal patients (CI: 1.5, 76.2), and 0.9 months in CSF positive patients (CI: 0.4, 2.0) (p = 0.009, Log rank test).