Clinical outcome of cerebrospinal fluid shunts in patients with leptomeningeal carcinomatosis

This retrospective review was based on the electronic medical records of 70 consecutive patients that underwent placement of either ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt for treatment of increased ICP or hydrocephalus secondary to LMC between 2002 and 2017 at a single institution, National Cancer Center, Korea. All patients were diagnosed by CSF cytology and had a suggestive or definite finding of LMC [16] on gadolinium-enhanced MRI. This retrospective study was reviewed and approved by the Institutional Review Board of the National Cancer Center of Korea (NCC2018-0043).

Seventy patients (40 females, 30 males) underwent shunt operation during the study period. All patients had extraventricular drainage or lumbar drainage to control increased intracranial pressure or to relieve headache before the shunt procedure. Disease preceding LMC was systemic cancer in 55 patients and primary brain tumors in 15 patients (Table 1). The systemic cancers were non-small cell lung cancer (NSCLC; n = 45), breast cancer (n = 6), leukemia (n = 2), cholangiocarcinoma (n = 1), and malignancy of unknown origin (n = 1). The primary brain tumors were high-grade glioma (n = 7), medulloblastoma (n = 5), primary neuroectodermal tumor (n = 2), and atypical teratoid/rhabdoid tumor (n = 1).

Fifty-one and 19 patients underwent VP shunt and LP shunt, respectively. There was no predilection for shunt type according to preceding disease. Forty-six patients (92%) with VP shunts and 13 patients (68%) with LP shunts had a programmable valve [that difference was because of late availability of programmable valves for LP shunt (since 2012)].

After shunt surgery, preoperative symptoms were “normalized” in 24 patients (34%), “improved” in 35 patients (50%), and “not improved” in 11 patients (16%). The type of shunt used (VP vs. LP), preceding disease (systemic metastases vs. primary brain tumor), and preoperative KPS score (≥ 70 vs. < 70) did not affect the clinical outcomes.

Median follow-up time was 3.3 (range, 0.2–43.0; 95% confidence interval, 3.47–6.93) months after the shunt. Neither peritoneal seeding nor secondary ascites were observed in all patients during the follow-up period. Seventeen patients (24%) underwent revision surgery due to malfunction or infection (eight patients each) or to intolerable over-drainage symptoms (one patient, case 17, Table 2). The average time between initial surgery and revision surgery was 1.1 ± 0.86 months. Six patients required a second revision surgery, and two needed a third revision.

Infections leading to revision surgery were due to skin contaminants in six patients, four of which had Staphylococcus epidermidis infection and a history of methotrexate intraventricular injection via Ommaya reservoir in the presence of LP shunt (cases 2, 3, 4, and 7). The other two patients had VP shunts and had Staphylococcus aureus infection at 1 month and 6 months after the shunt surgery, respectively, without any history of reservoir puncture before the infection (cases 1 and 8). One patient that was bedridden had a Candida albicans infection of an abdominal wound 2 weeks after LP shunt installation (case 6). Another patient had a Klebsiella pneumoniae infection 4 days after LP shunt installation (case 5). The infected LP shunts were removed and either re-inserted after infection control via the same route (four patients) or changed to a VP shunt (two patients). Two patients with VP shunt infection refused to undergo new shunt insertion.

Shunt malfunction occurred in eight patients. In four patients, shunt function study documented the malfunction site. Two patients with VP shunts and glioblastoma (case 9) and medulloblastoma (case 10) showed distal and ventricular catheter obstruction, respectively. No cancer cell obstruction but only myxoid material was found in the ventricular catheter from the patient with medulloblastoma. Two patients with LP shunts with fixed pressure-valve reservoirs had proximal catheter obstruction (case 14) and distal catheter leakage at the junction with the reservoir (case 16), respectively. In another two patients, X-ray examination revealed mechanical failures due to proximal catheter migration (case 11) and distal catheter malposition into the pre-peritoneal space (case 13), respectively. The remaining two patients had LP shunts with fixed pressure-valve reservoirs. Under-drainage was suspected in those patients because of deterioration before revision, although neither obstruction nor malfunction was found during revision surgery. One patient received a VP replacement shunt (case 12), and the other received an intraventricular Ommaya (case 15).

Revision surgery was more common in patients with LP shunts than in those with VP shunts because of the higher rates of malfunction (5/14 vs. 3/48, p = 0.017) and infection (2/49 vs. 6/13, p < 0.001) with the LP shunts. Five out of seven LP shunts with fixed pressure valve reservoirs malfunctioned, while all 12 LP shunts with programmable valves did not. A possible reason for the higher incidence of infection in the patients with LP shunts is that four out of 11 patients that received Ommaya intraventricular chemotherapy had S. epidermidis infection.

Five patients had medulloblastoma, and none of them showed any sign of peritoneal seeding during 2.9–40.3 months of follow-up.

Fifty-six patients (80%) died during follow-up, 27 (48%) because of LMC progression and 13 (23%) because of systemic disease progression. The cause of death was undetermined in 16 patients (29%). The median survival of all patients was 8.7 months (range, 0.2–52; 95% confidence interval (CI), 6.0–11.4; Fig. 1) after LMC diagnosis and 3.9 months (95% CI, 2.6–5.2) after initial shunt surgery.

Patients with LMC from systemic cancer had significantly shorter OS than patients with primary brain tumors (7.6 vs. 13.9 months, p = 0.03, Fig. 1b). Patients with breast cancer had longer OS than patients with NSCLC (17.2 vs. 7.6 months, p = 0.044).

The OS of patients with LMC from NSCLC (n = 45) was compared to patients from another set of patients (n = 46) with LMC from NSCLC who had increased ICP and received intraventricular chemotherapy (n = 105) but did not receive shunts in a historical data [17]. The OS of NSCLC patients with the shunt (7.6 months; 95% CI, 5.8–9.4) was significantly prolonged compared to that of NSCLC patients without the shunt (2.3 months; 95% CI, 1.6–3.0) (p < 0.001, Fig. 2).

Most studies reporting clinical results of CSF shunts in patients with LMC have focused on the analysis of LMC or CNS metastases, and few patients with those conditions receive shunt procedures [11, 18]. Omuro et al. [19] reviewed the outcomes of 37 patients with LMC from systemic cancer (excluding primary brain tumors) that received VP shunt for increased ICP and reported improvement of ICP-related symptoms in 27 patients (77%). Lee et al. [13] reported a similar improvement rate of 80% after VP shunt in patients with CNS metastases (40 patients with LMC and 10 patients with parenchymal brain metastases), noting improvement of headache (86% of patients), gait disturbance (71% of patients), cognitive dysfunction (40% of patients), and urinary incontinence (40% of patients). In the present study, 59 patients (84%) had improvement of preoperative symptoms, including 24 patients (34%) whose condition was “normalized.” Future studies will need to differentiate between symptoms caused by hydrocephalus and those caused by LMC (e.g., altered mentality) or brain tumors, in case of accompanying parenchymal mass lesions.

Despite the improvements in symptoms, some shunt surgeries resulted in revisions due to malfunction or infection. Complication rates following shunt procedures vary from 4 to 85% according to the shunt type (VP vs. LP), procedure (freehand vs. stereotactic), valve type (programmable vs. fixed), or chronology [20‐23]. In a nation-wide (the USA) study of revision rates after shunt surgery in 4480 patients with idiopathic intracranial hypertension from 2005 to 2009, Menger et al. reported that 3.9% of VP shunts and 7.0% of LP shunts (p < 0.0001) required revision [15]. The revision rate in patients with LMC appears to be higher than those figures. In this study, LP shunts with fixed pressure-valve reservoirs had the highest revision rate (5 out of 7) among the shunt and reservoir types; VP shunts malfunctioned in three out of 51 patients (5.9%). Omuro et al., who used only VP shunts for patients with LMC, reported that 8% of the shunts malfunctioned and required revision surgery. Neither the present study nor that of Omuro et al. found cancer cell obstruction of the shunt tubing or the reservoir. Another dangerous potential complication of CSF shunts is peritoneal seeding of cancer cells. To date, the documented cases of such seeding are mostly from medulloblastomas, which are well known to cause extra-neural metastases [14, 24, 25]. In those cases, the shunt was inserted before or after tumor removal, and peritoneal seeding occurred with or without primary tumor recurrence. Although the five patients with medulloblastoma in the present study had no documented shunt-mediated metastasis, such metastasis has been diagnosed up to 5 years after shunt placement [25].

VP shunt has been suggested to relieve increased ICP and to improve the OS of patients with LMC [6, 9, 11]. Omuro et al. reported median OS among 37 patients with LMC from systemic cancer as 2 months after the shunt and 4 months after diagnosis of LMC (range, 2 days to 3.6 years) [19]. Jung et al. reported that patients with LMC and hydrocephalus that received surgical treatment had longer OS than those that did not receive surgical treatment (5.7 months vs. 1.7 months), although the difference was not statistically significant because of the small numbers of patients (n = 7 and 11, respectively) [11]. In the present study, patients with LMC from systemic cancer showed a median OS of 7.6 months after diagnosis.

Both VP and LP shunting could safely divert CSF flow either from a ventricle or spinal arachnoid space to peritoneal space. Each type of shunt system has advantages and disadvantages, so the choice should be tailored to the patient’s condition. In general, LP shunting is confined to communicating hydrocephalus (HCP) and preferentially used in patients who are not suitable for cranial surgery (i.e., idiopathic intracranial hypertension with slit ventricle) or who want to avoid cranial surgery, whereas VP shunting can be used regardless of communicating or non-communicating HCP [15, 26]. Earlier-era LP shunts without adjustable valve reservoirs had problems in adjusting the amount of CSF drainage and assessing the shunt patency [27, 28]. Hence, LP shunts have been less frequently used than VP shunts. Those problems are much reduced since the advent of LP shunts with programmable valve reservoirs [29]. In the present study, all mechanical malfunctions of LP shunts occurred with the fixed-valve reservoir type; LP shunts with programmable valve reservoirs had revisions due only to infection.

Continuing intraventricular chemotherapy was tried in patients with LMC and a shunt. For those with VP shunt, CSF is directly drained into the peritoneal space from the ventricle, and therefore, a drug delivered intraventricularly would be mainly carried not into lumbar/cisternal CSF space but into the peritoneal space. To overcome this problem, on-off valve system had been tried in other studies for the purpose of enforcing drug delivery to lumbar/cisternal CSF space by closing the shunt [30]. However, we still have not had pharmacokinetic data that showed how much of the intraventricularly injected drug reached lumbar/cisternal CSF space during valve-off time in these patients who lost their physiologic CSF flow unless they injected the drug via lumbar puncture. In this study, we used a combination of Ommaya reservoir and LP shunt. Previously, this concurrent use of Ommaya reservoir and LP shunt was studied for the access to CSF space in the era of LP shunt without reservoir valve system. Zhang et al. reviewed the LP shunting in patients with LMC and suggested a hypothetical advantage of cooperative use of Ommaya reservoirs [31]. Eleven patients in the present study received an LP shunt in addition to a pre-installed Ommaya reservoir for the purpose of intraventricular chemotherapy. We measured lumbar methotrexate level from LP shunt reservoir in a patient and evaluated therapeutic concentration was achieved at approximated half-time of 2.3–4.2 h (data not provided). Four of those patients contracted S. epidermidis infections after intraventricular chemotherapy injection. Recent improvements in aseptic techniques of intraventricular chemotherapy injection have so far resulted in no further CSF infections in our institution.