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| ORIGINAL ARTICLE |
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| Ahead of print
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Triple intrathecal chemotherapy for leptomeningeal carcinomatosis in solid tumors: Treatment outcomes, response and their determinants
Vijay K Srinivasalu1, Narayana Subramaniam2, Arun Philip1, Wesley Jose1, Keechilat Pavithran1
1 Department of Medical Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| Date of Submission | 05-Nov-2018 |
| Date of Decision | 24-Oct-2019 |
| Date of Acceptance | 25-Oct-2019 |
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Correspondence Address:
Vijay K Srinivasalu,
Department of Medical Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/ijc.IJC_730_18
Background: Leptomeningeal carcinomatosis (LC) is the metastatic infiltration of leptomeninges by malignant cells originating from an extrameningeal primary tumor site, either extraneural or intraneural. In the absence of treatment, survival is usually measured in weeks, however with treatment this may be extended to a few months. Our institutional protocol has been to offer intrathecal chemotherapy (ITC) to patients having solid tumors with cerebrospinal fluid (CSF) cytology positive leptomeningeal carcinomatosis. This study was performed to describe the oncological outcomes in this cohort and their determinants.
Methods: A retrospective review of data of patients treated at Amrita Institute of Medical Sciences, Kochi, India was performed. Patients with CSF cytology positive solid tumors treated with triple ITC (methotrexate, cytosine arabinoside and hydrocortisone) were assessed for patient characteristics, treatment response, survival and the factors affecting them.
Results: Twenty patients of LC treated with triple ITC were included in the study. The median age of the study group was 49 years with a slight female preponderance (55%). All patients had positive CSF cytology with mean CSF glucose of 60 mg/dL, mean CSF protein of 92 mg/dL and mean cell count of 5. Breast cancer was the most common primary tumor (45%), followed by lung (35%) and stomach (5%). Symptomatic improvement was reported in 70% of patients after initiating ITC. Median overall survival (OS) at 6 and 12 months was 38% and 14%, respectively. Median progression-free survival (PFS) was 2 months. Patients with brain parenchymal metastasis had poor 6 month OS (25% vs 50%, P = 0.013) and 6 month PFS (0% vs 20%, P = 0.023).
Conclusion: A triple drug combination of methotrexate, cytosine arabinoside and hydrocortisone when given intrathecally for patients with LC showed good control of symptoms and reasonable survival. It may be beneficial in patients with no brain parenchymal involvement.
Keywords: Leptomeningeal metastases, treatment response, triple intrathecal chemotherapy
Key Message: Triple intrathecal chemotherapy with methotrexate, cytosine arabinoside and methotrexate has shown promising results in patients with brain metastasis from a solid tumor where standard chemotherapeutic drugs have failed to breach the rigid blood-brain barrier.
How to cite this URL:
Srinivasalu VK, Subramaniam N, Philip A, Jose W, Pavithran K. Triple intrathecal chemotherapy for leptomeningeal carcinomatosis in solid tumors: Treatment outcomes, response and their determinants. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297032 |
| » Introduction | |  |
Leptomeningeal carcinomatosis (LC) is the metastatic infiltration of leptomeninges by malignant cells that originate from an extrameningeal primary tumor site that may be extraneural or intraneural (the former being more common). The common primary tumors associated with LC arise from breast, lung (most commonly non-small-cell lung cancer [NSCLC]), the gastrointestinal tract, malignant melanomas, primary central nervous system (CNS) cancers (such as medulloblastoma, ependymoma, pineoblastoma, primitive neuroectodermal or primary CNS lymphoma), lymphomas (most often non-Hodgkin's Lymphoma), leukemia (mainly acute lymphoblastic leukemia [ALL]) and multiple myeloma.[1],[2],[3]
The presence of carcinomatous meningitis is usually a late manifestation of disease, and is associated with, a poor median overall survival of 2–3 months at diagnosis.[4],[5] The therapeutic intent in these patients is usually palliative, although newer therapies have been promising. Systemic chemotherapy has a limited ability to cross the blood-brain barrier (BBB), so these agents are often combined with radiation and other palliative surgical interventions. The goals of therapy include preventing neurologic deterioration, maintaining quality of life and prolonging survival.
Intrathecal chemotherapy (ITC) is frequently considered as a therapeutic option in LC for symptom control and improving the quality of life; however, prospective data is limited. Additionally, literature on the treatment of leptomeningeal carcinomatous from our country has been scarce. Our institutional protocol has been to offer ITC to patients having solid tumors with cerebrospinal fluid (CSF) cytology positive LC, and the purpose of this study was to assess these patients' characteristics, response to ITC and their determinants.
| » Materials and Methods | | |
Study setting and design
After institutional ethical committee clearance, from a prospectively maintained database of patients treated at Amrita Institute of Medical Sciences, Kochi, we identified 20 patients of LC from a histologically proven solid tumor who were treated with ITC between 2010 and 2014. LC was defined in patients with histologically proven solid tumors as having malignant cells identified in CSF cytology. Patients with hematological malignancies (including acute or chronic leukemia or lymphoid malignancy) were excluded. The chemotherapeutic regimen used was a combination of three drugs: methotrexate, cytosine arabinoside and hydrocortisone, all of which were administered intrathecally.
Information extracted from this database included age, gender, pathological stage according to the American Joint Committee on Cancer (AJCC) 7th edition, treatment details, CSF cytology before and after administration of ITC and brain parenchymal involvement. Overall survival (OS) was calculated from the date of diagnosis of LC to the date of death or last follow-up visit. Progression-free survival (PFS) was calculated from the date of diagnosis of LC to the date of proven disease progression.
Patient assessment
All patients were investigated with computerized tomography (CT) or magnetic resonance imaging (MRI) of brain, lumbar puncture with CSF cytology and routine biochemical investigations (including complete blood counts with coagulation profile, liver and renal function tests and serum electrolytes).
Treatment regimen
Under aseptic conditions, lumbar puncture (LP) was performed and ITC was administered. In patients with spine deformities or trauma to the spine or other reasons where LP could not be performed, an Ommaya reservoir was utilised for the administration of ITC. Triple ITC regimen contained methotrexate (12 mg for first dose followed by 10 mg in the subsequent dose), cytosine arabinoside (70 mg for first dose followed by 50 mg subsequently) with hydrocortisone (50 mg each dose). Multiple (≥3 lesions) intra-parenchymal brain lesions on MRI/CT were treated with whole-brain radiation therapy (WBRT) in combination with triple ITC.
CSF was obtained and examined before each cycle of chemotherapy. Serial examinations including cytology, complete cell count, differential count, glucose and protein were performed. Neurological status was assessed at the initiation of therapy and was reassessed before each cycle of chemotherapy. Neurological improvement was defined as a decrease in the intensity or disappearance of the initial neurological symptoms and signs, while a neurological response was defined as stabilisation of neurological signs or symptoms, or improvement persisting for at least 4 weeks.
Response assessment and adverse effect profile
The criteria for a cytological response included the complete clearing of all malignant cells from lumbar CSF in at least two serial examinations with demonstrable neurological improvement. Treatment sessions were repeated twice a week and patients were assessed for response by CSF cytology, with responders (those whose CSF showed no malignant cells or no atypical cells) receiving weekly maintenance therapy for at least 4 weeks with the same regimen until disease progression. To evaluate adverse effects, a complete blood cell count and biochemical profiles were monitored weekly.
Statistical analysis
Statistical analysis was performed using SPSS version 22 (IBM Corp, Armonk, NY). Categorical data was analysed using the Chi-square test. Survival curves were generated using the Kaplan–Meier method. All statistics were two-sided and P < 0.05 was considered statistically significant.
| » Results | | |
Patient and clinical characteristics
A total of 20 patients having solid tumors with LC were included in the analysis. The median age of the study group was 49 years with a slight female preponderance (55%). Breast (45%) and lung cancers (35%) were the most common primary tumors associated with LC in our cohort [Table 1]. The most common symptoms related to LC at presentation were headache, vomiting, loss of consciousness, cranial nerve palsies and seizures.
Response to treatment
All patients had positive CSF cytology at the time of diagnosis with a classic pattern of hypoglycorrhachia, hyperproteinorrhachia and malignant cells present. The mean CSF glucose was 60 mg/dL, mean CSF protein was 92 mg/dL and a mean cell count was 5 cells. After 2 weeks of initiation of therapy, 70% of the patients reported an improvement in symptoms. The response rate to triple ITC in terms of CSF clearance (defined as pretreatment positive CSF fluid testing negative for malignant cells on two consecutive occasions after 4 doses of biweekly triple ITC) was 65%.
Predictors of disease progression and survival outcomes
A univariate analysis was performed to correlate primary tumor site, patient age, baseline cell count on CSF cytology and involvement of brain parenchyma with disease progression. The only predictor of disease progression was brain parenchymal involvement by LC (P = 0.034) [Table 2].
The median OS at 6 and 12 months was 38% and 14%, respectively, with the median PFS being 2 months. Among patients with breast and lung cancer with LC, the median survival was 20 months and 15 months, respectively. Patients with brain parenchymal involvement had poorer 6 month overall survival (25% vs 50%, P = 0.013, [Figure 1]) and 6 month PFS (0% vs 20%, P = 0.023, [Figure 2]) when compared to those without. It is imperative to note, however, that all those with brain parenchyma involvement experienced an improvement in symptoms on ITC. | Figure 1: Overall survival in patients with and without brain metastases
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 | Figure 2: Progression-free survival in patients with and without brain metastases
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| » Discussion | | |
LC is an oncological emergency; these patients tend to have a dismal prognosis and poor quality of life, so early detection and initiation of therapy offer the best chance of alleviation of symptoms. The most common solid malignancies associated with LC in our study were adenocarcinomas of the breast (45%), NSCLC (35%) and adenocarcinoma stomach (15%), which were similar to the reported world literature.[4]
Headache and nausea associated with vomiting are predominant presenting symptoms in patients with LC, resulting from a raised intracranial pressure. Cranial nerve palsies with diplopia or visual disturbance (involvement of cranial nerves VI, III, IV, II) and hearing loss (involvement of cranial nerve VIII) are not uncommon at presentation. Other commonly reported symptoms in the literature were radicular symptoms (weakness, involuntary voiding of urine and cauda equina syndrome) and focal neck and back pain.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Nearly half the patients in our cohort had headaches and seizures. Four patients had cranial nerve palsies at presentation; facial nerve involvement in two and lower cranial nerve involvement (IX/X/XI/XII) in two.
CSF analysis still has great importance in the workup of LC.[16] All of our patients presented abnormalities in CSF and 75% of them presented with the classic pattern as described, reiterating the need for routine CSF analysis in order to screen patients at risk of LC.
Treatment in LC is purely palliative in intent, aimed at improving the quality of ilfe. Despite advances in treatment with radiation and chemotherapy, the median survival is 3-6 months with 1- and 2-year survival rates of 18% and 6%, respectively.[1],[17],[18] The median OS in our cohort at 6 and 12 months were 38% and 14%, respectively. The median PFS was 2 months. Median OS in patients with breast and lung cancers was 20 months and 15 months, respectively.
Standard chemotherapies administered to treat solid tumors do not penetrate the BBB, making treatment difficult. Chemotherapeutic drugs are usually hydrophilic and have less than 5% penetration into the BBB[4] whereas intrathecal delivery of chemotherapy bypasses the BBB and minimises systemic side effects. ITC is the mainstay of treatment for LC, but its effectiveness is limited and its superiority over systemic treatment has not been established in randomised trials. ITC mainly involves the injection of antitumor agents into the CSF, either directly into the lateral ventricle through a subcutaneous reservoir and ventricular catheter (like an Ommaya device) or into the lumbar thecal sac by LP. Recent studies have shown patients treated with intraventricular chemotherapy have better overall survival over those with administered chemotherapy via LP, when these resources are available.[19] The drugs most commonly used for ITC are methotrexate, standard cytarabine, and less often, thiotepa. Experimental agents including monoclonal antibodies are acquiring increasing importance.
Single-agent methotrexate has been shown to successfully clear malignant cells from the CSF in 20–61% of cases,[20],[21],[22] with the addition of intrathecal hydrocortisone showing a reduction in toxicity.[23] Several reports have described the use of other cytotoxic agents in sequence or in combination with methotrexate; however, they have failed to demonstrate a clear-cut advantage over monotherapy.[23],[24],[25] Liposomal cytarabine is also a preferred formulation in patients with LC as it has a CSF half-life of fewer than 4 hours and is entirely eliminated within 1–2 days.[10],[11] Sustained-release agents may be beneficial in this setting; a randomised controlled trial of 61 patients with LC comparing the efficacy of ITC sustained-release cytarabine to methotrexate found similar efficacy but significantly increased time to neurological progression and an easier-to-manage administration schedule for sustained-release cytarabine.[26],[27]
The advent of newer targeted therapies such as tyrosine kinase inhibitors (which have better intracranial penetrations in treatment of NSCLC) has led to better outcomes in patients with brain metastasis. Immunotherapies have also emerged as promising therapeutic options for several types of cancers including primary malignancies of the CNS and brain metastases. Several case reports have demonstrated decreased progression and improved prognosis of LC from breast cancer following intrathecal trastuzumab, a monoclonal antibody that targets malignant cells that overexpress HER2.[28],[29],[30],[31] However data on intrathecal immunotherapy administration is limited except in metastatic melanoma, where case studies have described the role of immune checkpoint blockade, intrathecal interleukin 2 (IL-2) or intrathecal tumor-infiltrating lymphocytes (TILs) therapies.[32]
One case reported a patient with melanoma-associated LC who received WBRT followed by ipilimumab and survived for more than 18 months.[33] There was also a report of radiographic LC mimicry in another melanoma patient treated with ipilimumab.[34] In a study of 42 patients with melanoma-associated LC treated with intrathecal IL-2, median survival was 9.1 (range 0.7–86.2) months with 16% of patients surviving for more than 24 months.[35] These are promising results when compared to the normal median survival of 10 weeks in patients with metastatic melanoma and LC.[13] Another case report revealed radiographic disease stabilisation in a patient with LC from metastatic melanoma after the administration of intrathecal autologous TILs in combination with intrathecal IL-2. Unfortunately, the regimen did not control the parenchymal brain metastases, which progressed 3 months following therapy.[36] Although findings such as these are encouraging, well-designed randomised controlled studies are needed to evaluate the efficacy of immunotherapies in these patients.
Performance status at the diagnosis of LC is one of the most important predictors of prognosis. Other frequently reported factors include primary tumor type, CSF protein levels, administration of combined modality treatment, systemic treatment or intra-CSF treatment and initial clinical or CSF response to treatment.[6],[7],[8],[9],[37],[38],[39] In our study, we found that the only poor predictor of survival was parenchymal brain involvement; other factors such as CSF cytology and protein, primary tumor type, CSF glucose levels were not found to be significant.
Aseptic or chemical meningitis is one of the more common complications observed, characterised by sterile CSF pleocytosis as well as clinical signs and symptoms of meningitis.[40],[41] In our study, 10% of the patients developed chemical meningitis, significantly less than the 43% reported in other studies, likely due to concomitant use of hydrocortisone.[40],[41] The most common hematological adverse effect in our study was myelosuppression, seen in 10% of the patients. None of the adverse effects encountered in our study was severe enough to discontinue therapy or mandate dose modifications. Other common complications of ITC in literature include leukoencephalopathy (particularly when combined with radiation), myelopathy and seizures, which we, fortunately, did not encounter.
Although the sample size of our study was limited due to the rarity of the diagnosis and the exclusion of hematolymphoid malignancies, there were some unique findings. The only predictor of poor survival in our cohort was brain parenchymal involvement; however, it is to be noted that even these patients experienced symptomatic relief on treatment. The incidence of chemical meningitis was also low in our cohort compared to literature, which is most likely due to our routine use of hydrocortisone.
ITC remains the mainstay of the treatment for LC, although its effectiveness may be limited. Although its superiority over systemic treatment has not been established in randomised trials, this study showed that our institutional protocol of biweekly triple ITC for patients was well tolerated and effective, achieving palliation either through delaying progression or by relief of symptoms.
| » Conclusion | | |
The triple-drug combination of methotrexate, cytosine arabinoside and hydrocortisone when given intrathecally for patients with LC showed good relief of symptoms with reasonable survival. It was well tolerated, with a significantly lower incidence of chemical meningitis when compared with other regimens. Although patients with brain parenchymal involvement had poor survival outcomes, the treatment still resulted in good symptom control.
Recent research indicates that the future in the treatment of LC is in the study of molecular-targeted therapies such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).[42] Further studies are required to optimise treatment outcomes in these rare but devastating sequelae of solid organ tumors.
Chemotherapy is the cornerstone of the treatment and intrathecal or intraventricular administration through Ommaya reservoir should be considered in these patients. Here, it is important to consider that the role of chemotherapy is to improve the neurological symptoms and quality of life rather than to prolong survival. Subsequent studies should focus on improving diagnostic and therapeutic options to reduce costs and exempt patients from invasive procedures.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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