Characteristics of the patients
Characteristics of patients who underwent SR or WBRT for their PBM are presented in . The median follow-up (of image) after index procedure was 6.0 months (range, 1-51 months), and the follow-up periods were not different according to the treatment modality with a median of 5.8 months for the WBRT group and 8.0 months for the SR group. The median survival of SR group was 14.5 months (95% CI; 10.5-28.7) and that of WBRT only was 9.4 months (95% CI; 7.4-11.9). However, this apparent difference of median survival between SR group and WBRT group was not statistically significant (p>0.05).
Characteristics of patients with who underwent surgical resection or whole brain radiation therapy for brain metastases of breast cancer
The median age of the patients at the time of the index procedure was 52 years (range, 28-80 years), and the median time from diagnosis of the primary cancer to brain metastasis was 41 months (range, 1-271 months). The median tumor volume was 4.0 cm3 (range, 0.01-105.0 cm3), and it was significantly different between two modes of treatment : the median tumor volume of the SR group was 10.9 cm3 while that of the WBRT group was 3.1 cm3 (p<0.001). Fifty-eight patients (32%) had a single lesion at the time of index procedure while the remaining 125 patients (68%) had multiple metastases. Patients with a single lesion were more frequently treated by SR than those with multiple lesions (p<0.001). Supratentorial lesions constituted 28% of the patients, and an infratentorial lesion occurred in 72% of the patient. Infratentorial lesion includes the case with both supratentorial and infratentorial brain metastases. Adjuvant chemotherapy after the index procedure was performed in 103 patients (56%) KPS was equal or greater than 70 in 90% of the patients. At the time of the index procedure, 118 patients (64%) had 'progressive' systemic disease and 65 patients had 'stable' disease or 'no evidence of disease (NED)'.
Analysis of factors affecting the incidence of LMC
LMC occurred in 27 out of 183 patients (14%) with the median time to LMC of 8.0 months (range, 2-26 months) (). LMC was diagnosed only by typical MRI findings for ten patients, only by cytology for two patients, and by both CSF cytology and MRI for the remaining 15 patients. After diagnosed with LMC, 15 patients received intra-CSF chemotherapy. Four patients received WBRT only with or without spinal radiation and the remaining 8 patients deferred any further treatment.
Fig. 1 Kaplan-Meier curve for time to development of LMC after treatment of the parenchymal brain metastases plotted for 183 patients in our study. Y-axis represents the proportion of patients without LMC at each follow-up time at the X-axis. 27 patients developed (more ...)
The distributions of the incidence of LMC according to various patients' characteristics and the hazard ratios of these factors based on cumulative LMC incidences are presented in .
Univariable analysis of factors possibly affecting the cumulative incidence of leptomeningeal seeding after surgical resection or whole brain radiotherapy for brain metastases
The incidence of LMC was significantly higher in the SR group than the WBRT group, as 10 of 27 (37%) patients were diagnosed with LMC. The hazard ratio (HR) for development of LMC in the SR group compared to WBRT was 2.95 (95% CI, 1.33-6.54; p=0.008) (). The incidence of LMC was higher in the younger age group (<40 years old) compared with that in patients aged 40 years or older as 8 out of 24 younger age patients developed LMC after the index procedure. However, the difference was not statistically significant at 0.05 (HR=2.36, 95% CI, 0.98-5.65, p=0.055). The time from diagnosis to brain metastasis (<12 versus ≥12 months), tumor volume (≤4.0 versus >4.0 mL3), number of lesions (single versus multiple), location of tumor (supratentorial versus infratentorial), adjuvant chemotherapy, KPS (≥70 versus <70) and systemic disease status (NED or stable versus progressing) were not significantly associated with the incidence of LMC in univariable analysis.
Fig. 2 Kaplan-Meier curves for time to development of LMC after treatment of the parenchymal brain metastases according to index procedure. Y-axis represents the proportion of patients without LMC at each follow-up time at the X-axis. Patients in the surgical (more ...)
Multivariable analysis of factors affecting the incidence of LMC
Among the factors analyzed univariately for the cumulative incidence of LMC, variables with a p-value less than 0.2 were included in the multivariable Cox proportional hazards model ().
Multivariable analysis of factors potentially affecting the cumulative incidence of leptomeningeal carcinomatosis after surgical resection or wholebrain radiation therapy
Among the preoperative characteristics, the index procedure was still significant and the younger age group gained statistical significance in this multivariable analysis. The administration of adjuvant chemotherapy and NED/stable systemic disease status significantly reduced the cumulative incidence of LMC in multivariable analysis even though these variables were not significant at the p-value 0.05 in the univariable analysis. Compared to the WBRT group, the HR of the SR group was 4.03 (95% CI, 1.51-10.73; p=0.005). The HR of the younger age (<40) group was 2.89 (95% CI, 1.16-7.19; p=0.022), adjuvant chemotherapy group decreased the risk for development of LMC at a HR of 0.43 (95% CI, 0.19-0.99; p=0.048), whereas patients with progressing systemic disease showed increased risk of LMC at a HR of 3.53 compared with NED or stable systemic disease (95% CI, 1.35-9.23; p=0.010).
Differential effects of the index procedure on the incidence of LMS according to the age group
To evaluate the differential effect of treatment modality on the development of LMC according to the age group, we performed the subgroup analysis presented in . For the different modes of treatment, WBRT group showed lower incidence of LMC in the old age (≥40) group (Fisher's exact test, p=0.005), whereas the difference according to the index procedure became not significant in the young age (<40) group due to high incidence of LMC regardless of the index procedures.
Differential effects of the index procedure on the incidence of LMC according to the age group