Gainor, Justin F. MD*; Ou, Sai-Hong Ignatius MD, PhD†; Logan, Jennifer NP, MS*; Borges, Lawrence F. MD‡; Shaw, Alice T. MD, PhD*
Departments of *Medicine, ‡Neurosurgery, Massachusetts General Hospital Cancer Center, Boston, Massachusetts; and †Department of Medicine, University of California, Irvine, Orange, California.
Disclosure: Dr. Shaw has served as a paid consultant for Pfizer, Ariad, Chugai, Novartis, and Daiichi Sankyo. Dr. Shaw has also received research funding from Pfizer, Ariad, Novartis, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Ignatius Ou has served as a paid consultant for Pfizer and has received research funding from Pfizer and Chugai. The other authors declare no conflict of interest.
Address for correspondence: Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer Center, 32 Fruit Street, Boston, MA 02114. E-mail: firstname.lastname@example.org
Anaplastic lymphoma kinase (ALK) gene rearrangements have emerged as important oncogenic drivers in non–small-cell lung cancer (NSCLC). Identified in 3% to 5% of patients, ALK rearrangements are associated with distinct clinical and pathologic features, such as younger age, light or never smoking history, and adenocarcinoma histology.1 In addition, ALK rearrangements confer sensitivity to treatment with the multitargeted ALK tyrosine kinase inhibitor crizotinib.2 In single-arm studies, crizotinib has been associated with an objective response rate of 60% and a median progression-free survival of 8 to 10 months.3 In a recently reported phase III trial (PROFILE 1007), ALK-positive patients treated with crizotinib in the second-line setting experienced statistically significant improvements in objective response rate and progression-free survival compared with those receiving standard, single-agent chemotherapy.4
In recent years, metastatic involvement of the central nervous system (CNS) has been recognized as an emerging complication in patients with ALK-positive NSCLC. In the PROFILE 1007 trial, for example, approximately 35% of ALK-positive patients had brain metastases at the time of study entry.4 In addition, several investigators have described the development of new or progressive brain metastases in patients receiving crizotinib.5–7 In this study, we expand on these reports and present a series of ALK-positive patients with two distinct forms of metastatic CNS involvement: intramedullary spinal cord metastasis (ISCM) and leptomeningeal carcinomatosis (LC).
Cases were identified through a clinical database of ALK-positive patients (n = 96) seen at the Massachusetts General Hospital between 2007 and 2013. All patients had advanced NSCLC. Medical records were reviewed to extract data on clinical features and treatment histories, including sites of disease. This study was performed through an Institutional Review Board–approved protocol.
Case 1 is a 31-year-old man with limited smoking history (10 pack-years) and stage IV NSCLC harboring an ALK rearrangement. He was treated with first-line cisplatin/pemetrexed/bevacizumab but experienced disease progression after four cycles. In October 2010, he began treatment with crizotinib, achieving a partial response. Crizotinib was continued until July 2012 when note was made of an enlarging gastrohepatic lymph node. Because of ongoing clinical benefit, crizotinib was continued beyond progression. In January 2013, however, the patient experienced acute neck pain and paresthesias in the left upper extremity after weightlifting. Symptoms of bowel and bladder dysfunction were absent. Magnetic resonance imaging (MRI) of the cervical spine revealed a 4.2-cm, T2-hyperintense mass in the cervical spine (C3–5), consistent with an ISCM (Fig. 1). Additional imaging also revealed a 3-mm intramedullary lesion in the thoracic spine (T12) and a 7-mm lesion within the putamen. A baseline MRI of the spine was unavailable; nevertheless, brain MRI at diagnosis showed no evidence of intracranial metastases. Neurosurgical interventions, including biopsy, were not recommended given the patient’s minimal baseline deficits and concerns for excess neurological morbidity related to any procedure. Crizotinib was discontinued and radiation therapy directed at C1–7 was initiated, resulting in improved pain and neurological symptoms. In May 2013, a repeat MRI of the cervical spine demonstrated an interval decrease in size of the cervical intramedullary lesion (Fig. 2).
Case 2 is a 37-year-old woman with a minimal smoking history (<1 pack-year) and stage IV NSCLC. Baseline tumor genotyping was negative for mutations in epidermal growth factor receptor (EGFR) and KRAS. She was treated with six cycles of first-line carboplatin/pemetrexed/bevacizumab, achi eving a near complete response. Thereafter, she received maintenance therapy with pemetrexed and bevacizumab. After 6 months of maintenance therapy, she developed disease progression in the right iliac crest and left lower lobe of the lung. A repeat biopsy was subsequently performed to obtain additional tissue for molecular characterization. This revealed an ALK rearrangement. She therefore began treatment with crizotinib and experienced a significant reduction in the size of her left lower lobe lung mass. A repeat computed tomography scan performed approximately 7 months after initiation of crizotinib demonstrated continued systemic disease control. Less than 1 week later, however, the patient developed nausea, vomiting, and a severe frontal headache requiring hospital admission. Of note, a brain MRI obtained 1 week before showed no evidence of brain metastases. The patient was examined by the neurology service, and a lumbar puncture was performed. Cytological evaluation of the cerebrospinal fluid (CSF) was positive for malignant cells, consistent with a diagnosis of LC. Despite initial symptomatic improvement after the lumbar puncture, she developed recurrent headaches, seizures, and worsening functional status. She was treated with analgesics and antiepileptics but was soon transitioned to supportive care. She died shortly thereafter.
Metastatic involvement of the CNS is a frequent complication in patients with lung cancer.8 Indeed, up to 40% of patients with NSCLC develop brain metastases during the course of their disease.9 Less often, however, lung cancer may involve other sites along the craniospinal axis, such as the spinal cord parenchyma (i.e., ISCMs) and the leptomeninges (i.e., LC).
In NSCLC, ISCMs are identified in less than 2% of patients, and less than 150 cases have been described in the medical literature.10,11 ISCMs are thought to arise predominantly through arterial dissemination although venous spread and direct invasion from contiguous structures have also been proposed.10 Development of ISCMs has also been attributed to meningeal spread in patients with concurrent LC, which has been reported in approximately 20% of patients with ISCMs.12
To date, descriptions of ISCMs in NSCLC have generally lacked tumor-genotyping information.10 In this study, we report the first case of ISCM in a patient with ALK-positive NSCLC. After identification of this index patient, three additional cases of ISCMs were found among 96 ALK-positive patients (4 of 96 or 4.17%) through a retrospective chart review (patients 2–4; Table 1). All four patients had a history of brain metastases; nevertheless, none had evidence of LC. The time interval from NSCLC diagnosis to development of ISCMs exceeded 15 months in all patients, suggesting that longer survival may place patients at increased risk for development of late complications, such as ISCMs. Notably, all four patients in this series were treated with radiation therapy. Nevertheless, the optimal treatment approach for patients with ISCMs has not been well defined, because most reports are retrospective and limited in size.10–12 In general, management strategies have included radiation therapy, surgical resection, chemotherapy, or a combination of these modalities.11
Like ISCMs, LC is a rare complication of lung cancer, identified in approximately 5% of patients.13 Recently, the incidence of LC seems to have increased, likely because of improved neuroimaging techniques and new, more effective systemic therapies. LC is thought to arise predominantly through hematogenous spread or through direct extension of parenchymal lesions.14 To date, only isolated descriptions of LC in ALK-positive NSCLC have been reported.5,15,16
After identification of the index patient described in case 2, we found four additional cases of LC among 96 ALK-positive patients (5 of 96 or 5.21%) through a retrospective chart review (patients 2–5; Table 2). All patients were symptomatic at the time of LC diagnosis, with the most common symptom being headache. In most cases, the diagnosis of LC was made based on cytological analysis of the CSF, which confirmed the presence of malignant cells. Interestingly, like ALK-positive patients with ISCMs, the time interval from NSCLC diagnosis to development of LC was fairly long (≥9 months in 4 of 5 cases), suggesting that LC may also be a late complication.
This series also raises important questions regarding the management of LC in ALK-positive patients. Currently, there is no defined standard of care for the treatment of LC in patients with NSCLC as a whole, and such patients have traditionally been excluded from clinical trial participation. Thus, the optimal approach for ALK-positive patients is also unclear.5,15,16 In general, treatment strategies have included intrathecal chemotherapy, systemic chemotherapy, surgery (e.g., ventriculoperitoneal shunts), or radiation therapy.13,14
It is noteworthy that a majority of patients in this series, both those with ISCMs and LC, had either previously received or were still being treated with crizotinib at the time they were diagnosed with these CNS complications (Tables 1 and 2). It has recently been shown that crizotinib administration produces low CSF to plasma ratios, suggestive of poor blood–brain barrier penetration.5 Furthermore, the brain seems to be among the most common sites of relapse in patients treated with crizotinib.3 Thus, it remains unclear whether development of ISCMs and LC in these cases reflects true biologic progression or a pharmacokinetic failure in the CNS.
Several next-generation ALK inhibitors are currently in clinical development. In early phase studies, several of these agents have shown activity in patients with brain metastases, perhaps reflecting increased potency and/or improved CNS penetration.17–19 For example, in a recent phase I/II study of the next-generation ALK inhibitor CH5424802, three ALK-positive patients were enrolled with untreated brain metastases.19 All three experienced responses in the brain after treatment with CH5424802, and two of three patients remained on therapy for more than 300 days without progression. Nevertheless, there is currently a lack of data on the rate and durability of CNS responses in patients treated with next-generation ALK inhibitors. It also remains unclear whether responses in the brain will translate into activity within other compartments of the CNS, such as the leptomeninges or spinal cord. Altogether, this underscores the need for CNS-specific cohorts within clinical trials of next-generation ALK inhibitors.
In summary, NSCLC patients with ALK rearrangements may present with metastatic involvement of sanctuary sites such as the brain, leptomeninges, and spinal cord. Clinicians should consider neuroimaging, including evaluation of the spine, in ALK-positive patients with neurologic symptoms. This report also highlights the need to develop novel ALK inhibitors with improved CNS penetration and antitumor activity.
Supported by a grant from the U.S. National Institutes of Health 5R01CA164273-02 and by a V Foundation Translational Research Grant.
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