Keywords
neurosurgery - leptomeningeal carcinomatosis - cerebrospinal - treatment
Palavras-chave
neurocirurgia - carcinomatose leptomeníngea - cefalorraquidiano - tratamento
Introduction
Leptomeningeal carcinomatosis (LC) was first reported in 1870 by the Swiss pathologist
Karl Joseph Ebert as an attack on the meninges by metastatic tumors.[1] In the first publication on this disease, Ebert highlighted that the absence of
localized signs and its variable nature made diagnosis difficult.[2] Then, in 1902, the term leptomeningeal carcinomatosis was proposed by Siefert, who
described its clinical presentation.[1]
Leptomeningeal carcinomatosis, also known as meningeal metastasis, is a consequence
of tumors that metastasize. The main tumors capable of evolving into a this metastasis
are lung cancer, breast cancer, and malignant melanoma.[3]
[4] The most common symptoms include headache, nausea, and vomiting.[5] Some cases may also include fever, relative devascularization, signs of meningeal
irritation, increased stiffness, and alteration of the cranial nerves; furthermore,
in more severe cases, convulsions and changes in the level of consciousness may occur.[3] It is well known that the majority of symptoms presented by patients are a consequence
of increased intracranial pressure (ICP) and the presence of hydrocephalus (HCP).
Moreover, the increase in ICP and HCP reduces the effectiveness of treatment (uneven
distribution of drugs given via intrathecal or intraventricular administration) and
contributes to a poor prognosis in patients with leptomeningeal carcinomatosis.[5]
Fig. 1 Image of V-Port.
The most important diagnostic measures are clinical evaluation, magnetic resonance
imaging (MRI), and analysis of the cerebrospinal fluid (CSF), as it is extremely important
to perform a full neurological examination to correctly identify the pathology.[6]
[7] Disease progression can be well demonstrated through MRI, which is considered useful
for the diagnosis of this disease.[8] Additionally, leptomeningeal carcinomatosis is being increasingly diagnosed in patients
with cancer due to improved detection through the routine use of MRI.[9]
[10] It is important to stress that, in some cases, the diagnosis may not be totally
accurate, when the disease is not suspected or when there are flaws in the imaging
examinations.[11]
The incidence of leptomeningeal carcinomatosis normally varies according to the type
of primary tumor, occurring in approximately 5 to 8% of patients with solid tumors
and 5 to 15% of patients with hematologic neoplasia. Although nearly all systemic
tumors metastasize into leptomeninges, the most common solid tumors in these instances
include lungs, breasts, and melanoma. Incidence by tumor type is 5 to 8% for metastatic
cancers of the breast, 9 to 25% for cancer of the lungs (greater in small-cell lung
carcinomas), and 6 to 18% for melanomas.[12]
As far as survival rates are concerned, approximately 10% may survive for a year,
though this varies according to the type of primary tumor.[6] However, neither age nor gender were related to survival.[13] On the other hand, the average survival period of leptomeningeal metastasis patients
who do not receive treatment is just 4 to 6 weeks, though survival may be extended
to between 4 and 6 months, depending on the treatment afforded.[11]
The available options for the treatment of leptomeningeal metastasis are intrathecal
(IT) chemotherapy, systemic therapy, radiotherapy, and surgery. In the case of HCP
or symptoms resulting from focal lesions, surgery, and radiotherapy are recommended.[11] The factors influencing the choice of treatment depend on the type of primary tumor
and the attack pattern of the disease. Accordingly, treatment must be personalized.[6]
Of the surgical methods available, the CSF shunt is an effective palliative procedure,
capable of alleviating the symptoms and improving patients' quality of life.[14]
[15] Various shunt types exist, including the ventriculoperitoneal shunt (VPS) and the
lumboperitoneal shunt (LPS). Both safely divert the flow of CSF from a ventricle or
spinal arachnoid space to the peritoneal space. The indication for each shunt type
should be made according to patients' condition, with the LPS being more suitable
when communicating HCP is involved, and when the patient cannot be subjected to cranial
surgery. The VPS, on the other hand, does not possess so many restrictions and may
be used regardless of whether the HCP is communicating or noncommunicating.[5]
Accordingly, the aim of this study is to perform a literature review on the role of
neurosurgery in the treatment of leptomeningeal carcinomatosis, to explain the advances
and new possibilities that have been emerging for the treatment of the disease in
the surgical setting.
Methodology
For the bibliographic review, a search of the PubMed database was made, encompassing
publications between 2011 and 2021. The following descriptors were employed: neurosurgery, leptomeningeal carcinomatosis, cerebrospinal, and treatment. In total, there were 42 results, from which 16 articles were selected. Among the
26 articles that were excluded, 25 did not involve surgical treatment, and 1 was unavailable.
Results
Of the 16 articles selected for the current review, 9 produced consistent results
and showed detailed data of the operations, as displayed in [Table 1], 7 dealt with VPS and LPS, 1 was a case report on the Ommaya reservoir, and 1 was
a case series study in respect of the V-Port.
Table 1
Description of operations found in the literature
|
Author
|
Type of study
|
Sample
|
Operation
|
Outcome
|
|
Zhao et al. (2017)
|
Retrospective analysis
|
6
|
Shunt
|
Alleviation of ICP, reduction in mortality and incapacity through intracranial hypertension,
and improved quality of life in patients with cancer.
|
|
Seon et al. (2019)
|
Retrospective analysis
|
70
|
Shunt
|
80% died during the follow-up period, 48% due to progression of the LC and 23% due
to progression of the systemic disease; the reason for death was unspecified in 29%
of cases. The VPS or LPS are effective for patients with HCP. There was an acceptable
level of complications.
|
|
Murakami et al.
(2018)
|
Clinical study
|
11
|
Shunt
|
An improvement in symptoms was observed in 9 patients, and severe headache relief
was reported in 7 of the 8 patients. This is an effective palliative surgical option
for alleviating the symptoms.
|
|
Lin et al.
(2011)
|
Retrospective case-control study
|
24
|
VPS
|
The insertion of the VPS resulted in a very low rate of postoperative complications
(8.3%), as well as the absence of infection and no perioperative deaths. The patients
enjoyed a longer overall average survival.
|
|
Yoshioka et al.
(2021)
|
Systematic review of case series
|
14
|
Shunt
|
The shunt is an effective procedure, including for the palliative treatment of HCP
symptoms.
|
|
Mitsuya et al. (2019)
|
Systematic review of case series
|
31
|
Shunt
|
There was a functional improvement of 90.3% in patients, with an increase in survival
of 3.5 months after shunt surgery.
|
|
Byun et al. (2018)
|
Case series
|
9
|
V-Port
|
This implantable reservoir was superior to the others as it is safe, easy to palpate
and more durable to large-bore needles.
|
|
Li et al.
(2020)
|
Case report
|
1
|
Ommaya reservoir
|
The Ommaya reservoir had a positive effect when used to administer IT chemotherapy.
|
|
Le Rhun et al. (2016)
|
Systematic review of case series
|
59
|
VPS
|
Symptoms improved in 93% of the patients; complications were observed in 11.8% of
the patients.
|
Abbreviations: HCP, hydrocephalus; ICP, intracranial pressure; IT, intrathecal; LC, leptomeningeal
carcinomatosis; LPS, lumboperitoneal shunt; VPS, ventriculoperitoneal shunt.
In terms of shunt insertion technique, according to the literature analyzed, an improvement
was seen in patients' conditions with increased rates of survival. In the retrospective
study conducted by Zhao et al., in which 6 individuals were assessed, it was possible
to note a reduction in intracranial hypertension, which consequently improved patients'
quality of life.[17]
Additionally, according to the retrospective analysis of Kim et al.,[5] and the systematic review of Yoshioka et al., analyzing 70 and 14 individuals respectively,
the shunt was effective in the treatment of HCP, improving patients' symptoms and
prolonging their life expectancy.
In the study published by Murakami et al.,[14] it was shown that 87.5% (⅞) of patients obtained an improvement in headaches after
the shunt had been inserted. Moreover, according to Lin et al.,[19] in their case-control study with a sample of 42 individuals, the insertion of the
shunt had a significant impact on increased patient survival rates. In the systematic
review conducted by Mitsuya et al.,[11] an average increase in life expectancy of 3.5 months was observed, postsurgery.
Thus, it is possible to determine that shunt surgery is effective in the treatment
of the signs and symptoms of leptomeningeal carcinomatosis. According to the results
of the study conducted by Le Rhun et al.,[10] the symptoms of 93% of patients improved on using the ventriculoperitoneal shunt.
Regarding complications involving shunt, the main ones listed by Kim et al.[5] involves hemorrhages, infections, shunt malfunction and risk of transferring cancerous
cells to the peritoneal region. In their study, 51 patients underwent VPS, and 19
LPS, with 8 patients developing infections. Additionally, there was a need to review
the procedure in 24% of the patients, either due to malfunction, infection, or symptoms
of excessive drainage; 6 patients required a second revision surgery and 2 required
a third.
As for the comparison of results obtained between the VPS and LPS, Kim et al.[5] observed that there was no significant difference in mean survival between patients
undergoing VPS and LPS procedures. On the other hand, patients who underwent LPS required
more evaluations for surgical revision, due to higher rates of malfunction and infection,
according to a study by Kim et al.[5] Therefore, in the review by Zhao et al.,[17] they pointed out advantages in cooperate the use of LPS with Ommaya reservoirs.
In the study by Li et al.,[18] the Ommaya reservoir was considered a safe option for administering IT chemotherapy,
all the more so when compared with administration via lumbar puncture. Other studies
did not note any complications relating to the Ommaya reservoir. The advantages include
it being a safer, more convenient procedure, with minimal pain for the patient and
the possibility of draining the CSF with the device, if necessary.
According to Byun et al.,[9] the average duration of surgery is 16 to 38 minutes. Regarding the main complications,
in the studies by Murakami et al.[14] and Magill et al.,[16] there were no reports of complications such as infection, misalignment or obstruction
of the tube, intracranial hematoma, or liquor fistula. The incidence of infection
was relatively low, all the more so when compared with the LPS, ranging from 5% to
8%. There was no need for revision surgery, in patients who received the Ommaya reservoir,
7.5% required revision surgery for VPS insertion due to an increase in ICP.
With the aim of refining the existing implantable reservoirs, Byun et al.[9] evaluated the V-Port ([Fig. 1]), which demonstrated better performance than all the other options. It stood out
on account of its safety and more simplified technical operation, with a low average
duration of operation (42 min) and smaller skin incisions. Furthermore, the study
did not observe complications such as infection, skin problems related to the V-Port,
or postoperative intracranial hypertension. As for the need for revision surgery,
out of a total of 9 patients, 7 (77.78%) were subjected to liquor drainage at least
once to control ICP, and 2 patients (22.22%) did not have ICP controlled by intermittent
drainage.
[Table 1] summarizes the principal operations analyzed, indicating the study type, sample
size, operation performed, and the respective outcome.
Discussion
Leptomeningeal carcinomatosis (LC) is the result of cancerous cells infiltrating the
meninges, bringing about aseptic inflammation in these structures.[17] The growth of these cells may be focal and/or diffuse, with the potential formation
of different sizes of nodule.[8] This condition continues to be one of the most challenging complications of cancer,
as it involves a complex diagnostic process, poor prognosis, negative impact on patients'
quality of life, and uncertain responses to cytotoxic treatment or standard targeted
therapy.[12]
Treatment
Treatment options for leptomeningeal carcinomatosis have been limited to the effective
administration of drugs, although not all patients achieve a good outcome with these
types of therapy. Therefore, after the disease is diagnosed, the ideal treatment continues
to be the consensus recommendation of specialists in the respective cases. However,
although treatment options remain limited, advances in molecular and genetic studies
into leptomeningeal carcinomatosis have been generating new, clinically effective
treatment options, and better ways to predict patients' response to treatment.[12]
Ommaya Reservoir
One of the treatment options for leptomeningeal carcinomatosis is the administration
of IT chemotherapy. This method manages to circumvent the blood-brain barrier and
minimize the systemic side effects. The drugs may be administered via lumbar puncture
or through the surgical insertion of a reservoir which, with the use of a catheter,
directly feeds the ventricular system (Ommaya reservoir). The most commonly used drugs
are methotrexate (a folate antagonist), thiotepa (an alkylating agent), cytarabine
(a pyrimidine analogue), and sustained-release liposomal cytarabine.[12]
In a retrospective analysis of 50 patients, 34 received treatment (IT chemotherapy
with liposomal cytarabine or methotrexate, systemic chemotherapy, or radiotherapy)
and 16 simply received support and palliative measures. The results showed that overall
average survival for patients receiving treatment was 21.2 weeks, compared with 6.38
weeks for patients who did not treat the disease.[13]
Various retrospective studies have demonstrated the positive impact on the survival
rates of patients receiving conventional chemotherapy treatment.[12] However, in the quest to find more effective drugs, the study conducted by Yoshioka
reported survival of a year for patients who received targeted molecular treatment
postoperatively, compared with 3.7 months for patients receiving only radiotherapy.
There are limitations to the conventional methods of antineoplastic treatments, given
that they are uncapable of attaining effective concentrations due to the blood-brain
barrier. Accordingly, Ommaya reservoirs tend to be more advantageous in administering
IT chemotherapy, both in terms of the operation and the safety of the patient.[18]
Thus, the insertion of an Ommaya reservoir for LC is a surgical option for the administration
of IT chemotherapy. However, one study found that 8 out of 107 patients (7.5%) who
received the Ommaya reservoir for LC-related HCP, required revision surgery to insert
a VPS due to the increase in ICP.[14]
Ventriculoperitoneal Shunt (VPS) and Lumboperitoneal Shunt (LPS)
As far as the surgical insertion of shunts is concerned, studies have shown that this
technique can alleviate symptoms arising from high ICP. Of the 5 patients treated
using shunt surgery, observed in a retrospective analysis, all of them displayed the
shunt in the computed tomography of the skull after the operation. The positioning
of the tube was correct and there was no operative bruising. Furthermore, no shunt-related
infections were reported for any of the patients.[17]
One study indicated there are three aspects that contribute to a better outcome after
shunting, namely: treatment with TKIs (Epidermal growth fator receptor [EGFR] tyrosine
kinase inhibitors), good ECOG (Eastern Cooperative Oncology Group) performance status
(the scale evaluates how the disease affects patients' everyday life skills) and controlled
extracranial cancer. Of the two shunt types, lumboperitoneal and ventriculoperitoneal,
the former is more effective in unfavorable conditions, precisely because it is less
invasive than the latter.[11]
The VPS technique was assessed in 59 patients suffering from leptomeningeal carcinomatosis
with a condition of HCP, 40 with brain metastasis and 19 with primary brain tumors.
The average duration of the surgery was 50.4 minutes. Symptoms improved in 93% of
the patients. Following an average follow-up of 6.3 months, 7 patients suffered complications
(11.8%). The average survival of patients who received the shunt was 6.4 months. The
LPS, which is less invasive, is also a good option for the treatment of intracranial
hypertension.[10]
Even though shunt surgery is a relatively simple neurosurgical procedure, the number
of patients receiving it is lower than the rate of increase in ICP. As the prognosis
of patients with LC is poor, for the most part the treatment of choice is not surgical
intervention. Moreover, complications with hemorrhaging, infection, shunt malfunction,
and the risk of transferring cancerous cells to the peritoneal region cause some doctors
to opt not to carry out CSF shunts on their patients.[5]
In one study, 70 patients who had previously had cancer (lung cancer, breast cancer,
among others) were analyzed. The main brain tumors were glioma and medulloblastoma.
A total of 51 patients received a VPS, while 19 had a LPS. Following surgery, preoperative
symptoms diminished in 35 patients, remained stable in 24, and did not improve in
11 patients. Shunt malfunctions and infections occurred in 8 patients, and 17 patients
had to be assessed due to shunt malfunction or excessive drainage. Average overall
survival was 8.7 months from the diagnosis of LC and 4.1 months after shunt surgery.[5]
Both the VPS and the LPS succeeded in safely diverting the flow of CSF from a ventricle
or spinal arachnoid space to the peritoneal space. Each shunt system has its advantages
and disadvantages, and, for this reason, the choice should be tailored to each patient.
In general, the LPS is used in cases of communicating HCP and in patients who are
not suitable for cranial surgery (i.e., idiopathic intracranial hypertension with
ventricular cleft) or who wish to avoid cranial surgery. The VPS, on the other hand,
can be used regardless of whether the HCP is communicating or noncommunicating.[5]
A study analyzed shunt surgeries performed on 11 patients with an average age of 58.
The average Karnofsky performance status (KPS) was 40; 8 patients (73%) were treated
with the VPS and 3 (27%) with the LPS. There were no reports of postoperative infections
in any of the patients. The average KPS was 60 after shunt surgery. Furthermore, none
of the patients developed infiltration of cancerous cells to the peritoneal region
after surgery.[14]
It may be concluded, therefore, that surgery to insert the VPS or LPS shunt is useful
for patients with HCP caused by LC, improving their symptoms and prolonging overall
survival.[5] The shunt proved to be an effective therapeutic procedure with regard to the alleviation
of symptoms given that 100% of patients showed improvedKPS.[15] Therefore, this procedure should be considered for palliative surgical treatment
of leptomeningeal carcinomatosis.[14]
Advances in Treatment
New improved techniques aiming to diverting CSF are in development, one of which is
the insertion of an on/off valve in conjunction with the programmable ventriculoperitoneal
valve (RO-VPS). The major advantage of this system is its reduced handling, as well
as enabling the management of the concentration of chemotherapy drugs in the CSF in
a more stable way.[19]
To overcome the obstacles involved with the Ommaya reservoir, Byun et al. developed
the V-port, which is equipped with a noncollapsible port with a titanium connector
where the ventricular catheter is inserted. This device is made out of polysulfones
and epoxy instead of silicon, making it more durable to the various bores and larger
needles, as well as being more easily palpated and having a lower risk of drug leakage.
It also stood out because of the short duration of operations reported by neurosurgeons,
the absence of complications resulting from the V-Port, and the lack of malfunction
complaints.[9]
Treatment Decision
Lastly, whenever viable, treatment with the intraventricular shunt was the preferred
option over IT therapy in the lumbar region, as per the study performed. In the event
of shortcomings with lumbar puncture, 22.5% preferred IT chemotherapy and only 15.5%
believed that radiotherapy should always be performed.[6]
Conclusion
Leptomeningeal carcinomatosis continues, therefore, to be a challenge to medicine
due to the difficulty of diagnosis and treatment. However, it should be noted that
the field of neurosurgery has been developing techniques capable of improving its
clinical condition and increasing both the quality of life and life expectancy of
patients. Furthermore, the available neurosurgical procedures have different purposes.
Shunts are considered an effective option in the management of HCP, while reservoirs
are used for infusion of drugs and are not very viable for the treatment of HCP. Therefore,
neurosurgery plays a significant role in the treatment of meningeal carcinomatosis,
precisely because it is able to improve the patients' prognosis.
