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Treatment planning and delivery
Treatment indication was discussed interdisciplinarily in the context of our institution’s comprehensive cancer center. Patients were selected individually for CSI according to clinically estimated benefit. Selection criteria qualifying for CSI were mild neurologic symptoms, young age, good clinical performance, favorable histology and limited or controlled systemic tumor burden in addition to systemic treatment availability. Patients with poorer clinical performance could receive CSI if they showed multifocally symptomatic spread and symptom improvement by CSI was deemed feasible. Total CSI was performed in 19 patients (76.0%) and subtotal CSI with a maximum total sparing of eight spinal segments in 6 patients (24.0%). Twenty patients (80.0%) received simultaneous CSI, while six patients had previously completed WBRT (sequential CSI). Nine patients had previously received dosimetrically relevant irradiation to parts of the CNS. In those cases, during CSI, the previously irradiated areas were spared or received a lower dose according to the remaining radiotolerance.
Helical IMRT at a TomoTherapy® (Accuray Inc., Sunnyvale, CA, USA) machine was used for CSI. An individual head fixation mask was fitted for each patient. Treatment planning was performed using a 5 mm computed tomography and gadolinium-enhanced magnetic resonance imaging when needed. Dose optimization aimed at a homogeneous dose distribution to all parts of the CNS, including the brain, simultaneously treating additional brain metastases, if existent. No dedicated sparing of intracranial organs at risk (eg, the hippocampus) was performed. All aspects of TomoTherapy planning for CSI have been described earlier.22 Five patients received treatment in part at a conventional linear accelerator using laterally opposing fields for cranial irradiation and multi-field three-dimensional conformal radiotherapy for spinal irradiation, as has been previously described.32,33Reasons were emergency start of treatment with subsequent TomoTherapy replanning, sequential CSI or subtotal CSI. The most commonly prescribed dose was 36 Gy in 20 fractions. Details on treatment parameters are presented in Table 2.
(To view a larger version of Table 2, click here.)
Statistical analyses
For baseline analyses, descriptive statistics were used. Continuous variables are given as means (SD) and/or median (IQR and range, as appropriate) and categorical variables as absolute and relative frequencies. The median follow-up time was calculated using the reverse Kaplan–Meier method.34Overall survival (OS) was calculated from the date of LC diagnosis to the last follow-up or death. OS was investigated using the method of Kaplan–Meier. Survival curves for prognostic factors were compared using a two-sided log-rank test. To identify the prognostic factors for OS, univariate and multivariate Cox regression were used. To preserve the validity of multivariate modeling in light of the limited number of patients, a maximum of three covariates that were significant in univariate analysis were chosen for multivariate Cox regression. The covariates thus chosen were the ones most frequently and strongly prognostic in comparable literature, while at the same time being easily and universally assessable in a clinical context. A univariate logistic regression was performed to screen for clinical factors with predictive value regarding symptom response to treatment (NFS stabilization or improvement, according to aforementioned definition). Since this was a retrospective exploratory data analysis, P-values are of descriptive nature. A descriptive P-value of <0.05 was considered as statistically significant. Statistical analyses were performed with the software R Version 3.4.3.
RESULTS
Survival and prognostic factors
Median follow-up, as calculated by the reverse Kaplan–Meier method, was not reached. At the time of analysis, 21 patients had died and 4 patients were still alive. Median OS in all treated patients was 19.3 weeks (IQR: 9.3–34.0). Actuarial follow-up at the time of median OS was 44% (Figure 1).
A KPI ≥70% at the beginning of RT was a significant prognostic factor for improved OS with a median OS of 28.3 weeks (IQR: 24.7–56.0) in patients with a good clinical performance (n=15, 60%), whereas patients with poor performance (KPI <70%, n=10, 40%) showed a median OS of 9.3 weeks (IQR: 7.3–11.7). This prognostic impact was shown in both univariate (HR 0.19, 95% CI: [0.07, 0.52], P=0.001) and multivariate (HR 0.13, 95% CI: [0.04, 0.40], P<0.001) analyses. Similar prognostic value was found for the patients’ age at LC diagnosis, with patients ≤55 years of age showing an improved median OS of 28.3 weeks (IQR: 15.7–47.9) in contrast to a median OS of 7.6 weeks (IQR: 5.7–25.7) for older patients. Again, the prognostic value of age confirmed in both univariate (HR 0.30, 95% CI: [0.11, 0.84], P=0.022) and multivariate (HR 0.21, 95% CI: [0.06, 0.77], P=0.018) analyses.
Patients initially presenting with mild or moderate symptoms (NFS ≤2) showed an improved OS in univariate analysis (HR 0.20, 95% CI: [0.06, 0.65], P=0.007). Median OS for these patients was 26.4 weeks (IQR: 11.7–47.9), compared to 9.3 weeks (IQR: 7.6–15.7) for patients presenting with severe neurologic symptoms. Symptom control or improvement in response to CSI was associated with a beneficial effect on OS (median 26.4 weeks, IQR: 15.7–47.9), whereas further neurologic deterioration during and after RT was prognostic for inferior OS (median 7.3 weeks, IQR: 5.7–16.0). The prognostic value of clinical response for improved OS was evident in univariate (HR 0.28, 95% CI: [0.10, 0.81], P=0.018) and multivariate (HR 0.24, 95% CI: [0.06, 0.92], P=0.037) analyses. Systemic treatment after CSI completion was administered in a total of nine cases (36.0%), and consisted of chemotherapy in five cases, targeted therapy in three cases and antihormonal therapy in one case. The application of systemic therapy after RT completion was prognostic for improved OS in univariate analysis (HR 0.34, 95% CI: [0.13, 0.90], P=0.029). The presence of CSF flow obstruction was prognostic of inferior OS (HR 3.02, 95% CI: [1.14, 7.98], P=0.026), whereas CSF protein levels below 100 mg/dL were prognostic of superior OS in univariate analysis (HR 0.16, 95% CI: [0.03, 0.73], P=0.018).
Clinical parameters without statistically significant impact on OS in our current analysis were the overall applied biologically equivalent dose and the extent of meningeal spread, involving only the spinal or additionally intracranial meninges. Furthermore, the presence or absence of parenchymal brain metastases, extracerebral metastases, nodular/bulky disease as well as the interval between primary and LC diagnoses showed no significant impact on survival. The clinical factors considered for univariate and multivariate analyses, the corresponding P-values and HRs are listed in Table 3. Age <55 years at LC diagnosis, KPI ≥70% at LC diagnosis and neurologic response to CSI were considered for multivariate analysis, according to the aforementioned rationale. Kaplan–Meier survival curves stratified by prognostic factors significant in the multivariate analysis are shown in Figures 2–4.
