Toxicity and symptom response

Acute treatment-related toxicity consisted mainly of nausea, fatigue and skin erythema. Those symptoms were mild and became manifest during treatment or within the first 4 weeks from treatment completion. Fatigue and nausea were most common among these symptoms, affecting 21 (84.0%) and 9 (36.0%) patients, respectively. None of these treatment-associated symptoms were considered severe or unexpected, and they were rated grade I or II according to CTCAE v 4.0. Of 25 patients, 20 (80.0%) patients completed the treatment and in 5 cases, treatment was discontinued due to tumor-associated general clinical deterioration. Prophylactic or therapeutic corticosteroids were administered in all patients, and all patients developed complete alopecia in the context of WBRT. Regular blood samples were taken for the early detection of high-grade myelosuppression which was defined as follows: anemia with hemoglobin levels <8 g/dL, neutropenia with leukocyte levels <1.0/nL or thrombopenia with thrombocyte levels <50/nL. Such hematologic toxicity, rated grade III according to CTCAE, was developed by eight patients (32.0%), who required medical intervention under which it was controlled. Six of these patients did not receive any systemic therapy after CSI. As far as can be determined in the context of this retrospective analysis, reasons in all these cases were either general performance related or due to the lack of efficacious medicamentous options. None was directly related to hematologic toxicity. No treatment-associated toxicities of grade IV or V were observed. Details on treatment-related toxicity are given in Table 4.

According to NFS, the majority of patients (n=19, 76.0%) initially presented with mild to moderate neurologic impairments (NFS 1–2). Severe neurologic impairment (NFS 3–4) was observed in six patients (24.0%). No patient was asymptomatic at the initial presentation. Most common among the documented symptoms were motor and/or sensory deficits (80.0% and 68.0%, respectively), often having led up to LC diagnosis. Headaches and vomiting as a sign of cerebral edema and elevated intracranial pressure (ICP) were frequent in patients presenting with additional brain metastases and were observed in 24.0% (n=6) and 16.0% (n=4) of the patients, respectively. Visual deficits and seizures affected 36.0% (n=9) and 12.0% (n=3) of the patients, respectively.


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Regarding the clinical outcome and response to CSI, a stabilization of individual symptoms could be achieved in 44.0%–80.0% of the patients, depending on symptom. ICP-related symptoms were most commonly controlled (76.0%–80.0%) or even improved (16.0%–16.0%) by WBRT. Motor deficits were improved in 36.0% and sensory deficits in 20.0% of the patients. Those symptoms were stabilized in 44.0% and 68.0% of the patients, respectively. However, a fraction of the patients (20.0% for motor deficits and 12.0% for sensory deficits) suffered further symptom deterioration, irrespective of the treatment. Considering overall NFS, symptom palliation in the form of stabilization could be achieved in 40.0% and a sizeable improvement in 28.0% of all patients. Details on symptom response are given in Table 5.

(To view a larger version of Table 5, click here.)

Positive predictive relevance for symptom response, as determined by the univariate logistic regression, was observed for age ≤55 years (OR 14.00, 95% CI: [2.13, 138.42], P=0.011), whereas the presence of CSF flow obstruction was a significant negative predictor (OR 0.13, 95% CI: [0.02, 0.79], P=0.034). A trend toward negative predictive impact was detected for the presence of metastases outside the CNS, but significance was not reached (OR 0.19, 95% CI: [0.03, 1.07], P=0.069). ORs and the corresponding P-values of univariate logistic regression for the endpoint of symptom response are listed in Table 6.

DISCUSSION

We retrospectively assessed our experience with 25 patients who received CSI as a palliative treatment for LC over a period of 10 years. Overall, from a technical, as well as clinical point of view, treatment was feasible and resulted in OS rates that compare favorably to those described in the literature for this patient collective.13,14 Acute treatment-related toxicity was moderate and palliative symptom control or improvement was achieved in the majority of patients. Despite the limited number of subjects, we were able to identify age at LC diagnosis, clinical performance and neurologic treatment response as independent prognostic factors for survival, potentially helping in terms of future patient selection.

Regarding the published literature, very little data is available on the subject of CSI for the palliative treatment of LC. To the best of our knowledge, only one other report has specifically evaluated this approach in the past 20 years: Hermann et al reported on their experience treating a total of 16 patients between 1995 and 2000.24 They achieved a median OS of 12 weeks and symptom palliation in 68% of the patients. The symptoms that most commonly improved were pain, motor impairments and bladder/bowel incontinence. Reported treatment-related side effects were manageable and included mucositis, nausea and dysphagia. One-third of the patients developed high-grade myelosuppression.24

The current National Comprehensive Cancer Network (NCCN) guidelines recommend CSI for LC only for highly select cases (eg, hematologic malignancies, breast cancer) due to this treatment’s toxicity profile.35 In general, if the neurologic status and clinical performance are adequate, ITC is the recommended treatment option for non-adherent LC, as stated in the European Association of Neuro-Oncology–European Society for Medical Oncology guidelines.3,10 Treatment is usually administered via an intraventricular catheter connected to a subcutaneous reservoir (Ommaya reservoir).36 Efficacy has been demonstrated for different agents: several randomized trials have established the role of high-dose methotrexate for LC from breast cancer, lymphoma and leukemia,17,19 as well as the roles of thiotepa and rituximab in hematologic malignancies.17,37 In breast cancer patients, methotrexate, topotecan, etoposide and trastuzumab were shown to be effective.37–39 According to the NCCN guidelines, the administration of RT is recommended mainly to the involved regions in order to achieve symptom palliation, address bulky disease and remove CSF flow obstruction.4,35

One of the main obstacles, which in the past limited the feasibility of CSI and resulted in substantial toxicity, was the use of non-conformal, non-image-guided RT techniques. At a conventional linear accelerator, treatment planning for CSI typically included two opposing fields for cranial irradiation and two dorsal fields for spinal irradiation.24 To achieve vertical RT field extension, including the entire spine, field junctions were necessary with the associated risk of field overlap or underdosage due to positioning errors. To compensate for those risks, craniocaudal field borders were shifted in regular intervals over the course of RT.24 The introduction of TomoTherapy resolved the problem of field junctions, since the continuous movement of the treatment couch during beam administration results in a helical application of the dose, achieving homogeneous dose distributions over a long vertical field extension.40,41 Combined with the use of IMRT, high-dose conformity can be achieved and dosimetric superiority over conventional RT techniques has been conclusively demonstrated for TomoTherapy in several studies.42–44 This allows for the effective sparing of organs at risk, substantially reducing treatment-associated toxicity. Improvements could be achieved regarding the occurrence and severity of mucositis, as well as pulmonary and hematologic toxicity.22,45,46 Regarding hematologic toxicity, however, the wider low-dose distribution of TomoTherapy may, in some cases, result in an increase of red bone marrow exposed to relevant low-dose irradiation (the so-called dose-bath effect).47 Modern linear accelerators can perform IMRT employing alternate techniques such as volumetric modulated arc therapy, achieving a similarly favorable reduction of toxicity.48 Several comparative studies between TomoTherapy and other IMRT techniques have been performed and overall, the resulting dose distributions provide adequate sparing of organs at risk for both techniques.48,49 Regarding field junctions, different techniques have been conceived to compensate for the positioning errors and avoid relevant over- or underdosage: exploiting the advantages of IMRT, low-gradient junction techniques, as well as non-coplanar IMRT techniques were proven effective dosimetrically.50,51 Superior sparing of bone marrow in the vertebral bodies, as well as even higher dose conformity can be achieved using proton irradiation.29,52 Favorable results regarding toxicity and tumor control have been described for proton CSI in pediatric tumors in several recent works, although proton therapy generally reintroduces the issue of field junctions.53–55