ABSTRACT
BACKGROUND: Leptomeningeal carcinomatosis (LC) is a severe complication of metastatic tumor spread to the central nervous system. Prognosis is dismal with a median overall survival (OS) of ~10-15 weeks. Treatment options include radiotherapy (RT) to involved sites, systemic chemo- or targeted therapy, intrathecal chemotherapy and best supportive care with dexamethasone. Craniospinal irradiation (CSI) is a more aggressive radiotherapeutic approach, for which very limited data exists. Here, we report on our 10-year experience with palliative CSI of selected patients with LC. PATIENTS AND METHODS: Twenty-five patients received CSI for the treatment of LC at our institution between 2008 and 2018. Patients were selected individually for CSI based on clinical performance, presenting symptoms and estimated benefit. Median patient age was 53 years (IQR: 45-59), and breast cancer was the most common primary. Additional brain metastases were found in 18 patients (72.0%). RT was delivered at a TomoTherapy machine, using helical intensity-modulated radiotherapy (IMRT). The most commonly prescribed dose was 36 Gy in 20 fractions, corresponding to a median biologically equivalent dose of 40.8 Gy (IQR: 39.0-2.5). Clinical performance and neurologic function were assessed before and in response to therapy, and deficits were retrospectively quantified on the 5-point neurologic function scale (NFS). A Cox proportional hazards model with univariate and multivariate analyses was fitted for survival. RESULTS: Twenty-one patients died and four were alive at the time of analysis. Median OS from LC diagnosis was 19.3 weeks (IQR: 9.3-34.0, 95% CI: 11.0-32.0). In univariate analysis, a Karnofsky performance scale index (KPI) ≥70% (P=0.001), age ≤55 years at LC diagnosis (P=0.022), cerebrospinal fluid (CSF) protein <100 mg/dL (P=0.018) and no more than mild or moderate neurologic deficits (NFS ≤2; P=0.007) were predictive of longer OS. So were the neurologic response to treatment (P=0.018) and the application of systemic therapy after RT completion (P=0.029). The presence of CSF flow obstruction was predictive of shorter OS (P=0.026). In multivariate analysis, age at LC diagnosis (P=0.018), KPI (P<0.001) and neurologic response (P=0.037) remained as independent prognostic factors for longer OS. Treatment-associated toxicity was manageable and mostly grades I and II according to the Common Terminology Criteria for Adverse Events v4.0. Eight patients (32%) developed grade III myelosuppression. Neurologic symptom stabilization could be achieved in 40.0% and a sizeable improvement in 28.0% of all patients. CONCLUSION: CSI for the treatment of LC is feasible and may have therapeutic value in carefully selected patients, alleviating symptoms or delaying neurologic deterioration. OS after CSI was comparable to the rates described in current literature for patients with LC. The use of modern irradiation techniques such as helical IMRT is warranted to limit toxicity. Patient selection should take into account prognostic factors such as age, clinical performance, neurologic function and the availability of systemic treatment options.
ABSTRACT
Introduction: The purpose of this article is to report our institution's 10-year experience on palliative radiotherapy for the treatment of leptomeningeal carcinomatosis (LC), assessing survival, neurologic outcome, and prognostic factors. Patients and methods: We retrospectively analyzed 110 patients who received palliative radiotherapy for LC between 2008 and 2018. The most common histologies were breast cancer (n = 43, 39.1%) and non-small cell lung cancer (NSCLC) (n = 31, 28.2%). Radiotherapy was administered as whole-brain radiotherapy (WBRT) (n = 51, 46.4%), focal spinal RT (n = 11, 10.0%) or both (n = 47, 42.7%). Twenty-five patients (22.7%) were selected for craniospinal irradiation. Clinical performance and neurologic function were quantified on the neurologic function scale (NFS) before and in response to therapy. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for survival. Results: Ninety-eight patients (89.1%) died and 12 (10.9%) were alive at the time of analysis. Median OS from LC diagnosis and from the beginning of RT was 13.9 weeks (IQR: 7.1-34.0) and 9.9 weeks (IQR: 5.3-26.3), respectively. In univariate analysis, prognostic of longer OS were a Karnofsky performance scale index (KPI) of ≥70% (HR 0.20, 95%-CI: [0.13; 0.32], p < 0.001), initially moderate neurological deficits (NFS ≤2) (HR 0.32, 95% CI: [0.19; 0.52], p < 0.001), symptom response to RT (HR 0.41, 95%-CI: [0.26; 0.67], p < 0.001) and the administration of systemic therapy (HR 0.51, 95%-CI: [0.33; 0.78], p = 0.002). Prognostic of inferior OS were high-grade myelosuppression (HR 1.78, 95% CI: [1.06; 3.00], p = 0.03) and serum LDH levels >500 U/l (HR 3.62, 95% CI: [1.76; 7.44], p < 0.001). Clinical performance, symptom response and serum LDH stayed independently prognostic for survival in multivariate analysis. RT was well-tolerated and except for grade III myelosuppression in 19 cases (17.3%), no high-grade acute toxicities were observed. Neurologic symptom stabilization was achieved in 83 cases (75.5%) and a sizeable improvement in 39 cases (35.5%). Conclusion: Radiotherapy is a well-tolerated and efficacious means of providing symptom palliation for patients with LC, delaying neurologic deterioration while probably not directly influencing survival. Prognostic factors such as clinical performance, neurologic response and serum LDH can be used for patient stratification to facilitate treatment decisions.
ABSTRACT
BACKGROUND: Characterization of combination effects of chemotherapy drugs with carbon ions in comparison to photons in vitro. METHODS: The human colon adenocarcinoma cell line WiDr was tested for combinations with camptothecin, cisplatin, gemcitabine and paclitaxel. In addition three other human tumour cell lines (A549: lung, LN-229: glioblastoma, PANC-1: pancreas) were tested for the combination with camptothecin. Cells were irradiated with photon doses of 2, 4, 6 and 8 Gy or carbon ion doses of 0.5, 1, 2 and 3 Gy. Cell survival was assessed using the clonogenic growth assay. Treatment dependent changes in cell cycle distribution (up to 12 hours post-treatment) were measured by FACS analysis after propidium-iodide staining. Apoptosis was monitored for up to 36 hours post-treatment by Nicoletti-assay (with qualitative verification using DAPI staining). RESULTS: All cell lines exhibited the well-known increase of killing efficacy per unit dose of carbon ion exposure, with relative biological efficiencies at 10% survival (RBE10) ranging from 2.3 to 3.7 for the different cell lines. In combination with chemotherapy additive toxicity was the prevailing effect. Only in combination with gemcitabine or cisplatin (WiDr) or camptothecin (all cell lines) the photon sensitivity was slightly enhanced, whereas purely independent toxicities were found with the carbon ion irradiation, in all cases. Radiation-induced cell cycle changes displayed the generally observed dose-dependent G2-arrest with little effect on S-phase fraction for all cell lines for photons and for carbon ions. Only paclitaxel showed a significant induction of apoptosis in WiDr cell line but independent of the used radiation quality. CONCLUSIONS: Combined effects of different chemotherapeutics with photons or with carbon ions do neither display qualitative nor substantial quantitative differences. Small radiosensitizing effects, when observed with photons are decreased with carbon ions. The data support the idea that a radiochemotherapy with common drugs and carbon ion irradiation might be as feasible as respective photon-based protocols. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.
