- Email: [email protected]
Leptomeningeal Carcinomatosis in Colorectal Cancer: The Mayo Clinic Experience
Original Study
Leptomeningeal Carcinomatosis in Colorectal Cancer: The Mayo Clinic Experience Gretchen Taylor,1 Nina Karlin,2 Thorvardur R. Halfdanarson,3 Kyle Coppola,2 Axel Grothey3 Abstract Leptomeningeal carcinomatosis is an uncommon metastatic progression of colorectal cancer. A database search of 17,095 primary colorectal cancers in a 15-year period returned 10 cases of leptomeningeal metastasis in these patients. Our series describes their disease course and outcomes. Leptomeningeal carcinomatosis confers a poor prognosis, with most patients receiving palliative therapies after the diagnosis was made. Background: Leptomeningeal metastasis (LM) is an uncommon form of metastatic disease in many cancers. There remains a paucity of literature with regard to the course and management of LM in colorectal cancers (CRCs). The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. Median overall survival after CRC diagnosis was 25.7 months (range, 4.7-74.8 months). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range, 0-68.1 months). All patients had magnetic resonance imaging findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, and 1 with both. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in 2 cases. Seven patients (78%) had palliative radiotherapy for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks). Conclusions: LM is an exceedingly rare development in the natural course of CRC. It confers a poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving radiotherapy to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Gastrointestinal, Neoplastic meningitis, Nervous system metastases, Oncology, Rare
Introduction Leptomeningeal carcinomatosis (LM), or neoplastic meningitis, is an uncommon metastatic complication of solid tumor progression. Most commonly arising from breast, nonesmall-cell lung cancer, and melanoma with a frequency of 5% to 25%,1 its incidence in colorectal 1
Department of Internal Medicine, Mayo Clinic Arizona, Scottsdale, AZ Division of Hematology-Oncology, Mayo Clinic Arizona, Phoenix, AZ 3 Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN 2
cancer (CRC) is far less than 1%.2 Suspicion for central nervous system (CNS) metastasis is raised when a patient presents with new neurologic complaints in the setting of a metastatic cancer. Gadoliniumenhanced T1-weighted magnetic resonance imaging (MRI) remains the most sensitive imaging diagnostic tool, with LM defined by abnormal leptomeningeal enhancement or small subarachnoid nodules.3 The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases.
Submitted: Aug 25, 2017; Revised: Oct 19, 2017; Accepted: Nov 14, 2017 Address for correspondence: Gretchen Taylor, MD, Department of Internal Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clcc.2017.11.003
Methods Institutional review board approval and waiver of consent were granted for an electronic medical records search. The Cancer
Clinical Colorectal Cancer Month 2017
-1
2
Gender
Year of Primary Diagnosis
1
F
2008
2
M
2007
3
F
2000
4
F
2001
5
M
2003
6
F
2003
7
M
8
9a
Patient
TNM Stage at Diagnosis
Treatment of Primary Cancer
Adenocarcinoma, moderately differentiated Adenocarcinoma with signet ring cell features; invasive, grade 3-4
T3N0M0
Resection; 5-FU; FOLFOX; capecitabine Resection; FOLFOX; 5-FU
Adenocarcinoma invasive, grade 3 Mucinous adenocarcinoma invasive, grade 2 Mucinous adenocarcinoma invasive, grade 3
TxNxM1
Pathologic Type
T3N0M0
Time to Metastasis, wk 88 133
T3N1M0
Resection (palliative); 5-FU; CPT-11 Resection; CPT-11, oxaliplatin Resection
6
Mucinous adenocarcinoma, grade 2
T3N1M0
Resection; 5-FU
56
2006
Adenocarcinoma invasive, grade 4
TxN1Mx
RT, 5-FU
0
F
2002
Adenocarcinoma invasive, grade 2
T3NxMx
Neo-adj RT, 5-FU; resection
26
M
2009
Adenocarcinoma invasive, poorly differentiated
TxNxM1
WBR, RT; FOLFOX þ Avastin
3
T2N2Mx
0 0
Treatment of Recurrence
Sites of Metastases
Year LM Diagnosed
Time to LM From Initial Diagnosis, mo
FOLFIRI þ Avastin; regorafenib Resection (liver); FOLFOX; capecitabine; RT; FOLFIRI þ bevacizumab; capecitabine þ bevacizumab; CPT-11 þ cetuximab; regorafenib; Rad-223 N/A
Liver, lung
2013
65.7
Liver, vertebra
2013
68.1
Liver, lung
2000
8.7
Liver, mediastinum, brain Nodal (supraclavicular, periaortic), axial skeleton, brain Liver, brain
2005
48.3
2004
6.7
2005
25.3
Nodal (pelvic, retroperitoneal, supraclavicular, subcarinal) Brain
2006
3.4
2005
36.7
2009
0
Resections (mediastinum, brain); WBR 5-FU, oxaliplatin; WBR
Resection (liver); FOLFOX, Avastin; CPT-11; resection (brain); WBR N/A
Resection (brain); WBR; Xeloda; RT; CPT-11; resection (brain, 2nd and 3rd) N/A
Axial skeleton, adrenal, brain
Abbreviations: CPT-11 ¼ irinotecan; F ¼ female; FOLFIRI ¼ combined 5-FU, leucovorin, irinotecan; FOLFOX ¼ combined 5-FU, leucovorin, oxaliplatin; 5-FU ¼ 5-fluorouracil; LM ¼ leptomeningeal metastasis; M ¼ male; RT ¼ radiotherapy; WBR ¼ whole brain radiation. a Patient No. 9: Concurrent lung adenocarcinoma found on bronchoalveolar lavage at time of initial work-up.
Leptomeningeal Carcinomatosis in CRC
Clinical Colorectal Cancer Month 2017
Table 1 Primary Colorectal Cancer History
Gretchen Taylor et al Registry identified all CRC primaries diagnosed between the years of 2000 and 2014 at our institution. The medical record numbers of these cases were then sent to 2 institutional data groups with a request to identify the concurrent diagnosis of LM. First, International Classification of Diseases, Ninth Revision code searches for “198.4: secondary malignant neoplasm of other parts of the nervous system” and “349.2: disorders of meninges, not elsewhere classified” was undertaken. The second data group was tasked with a term search within the medical records of these patients with CRC. They queried cytology reports of cerebral spinal fluid analysis for the terms “leptomeningeal carcinomatosis,” “carcinomatous meningitis,” “neoplastic meningitis,” “leptomeningeal cancer,” “leptomeningeal metastasis,” “leptomeningeal carcinoma,” and “meningeal metastasis.” In addition, all biopsies of a CNS mass in a patient with CRC were identified, and those pathology cases were flagged for further review if the report included the term “metastatic.” The data group also queried the electronic database for imaging reports of the brain, head, spine, vertebra, and sinuses (MRI, magnetic resonance angiography, computed tomography, positron emission technology) for the terms “leptomeningeal” or “leptomeninges” in the cases of patients with CRC. The medical record review yielded 93 unique cases, which were sent to the research clinicians for further review. Of these cases, 64 had a billing diagnosis of either 198.4 or 349.2. Of the 93, there were 29 unique cases with an imaging report flagged for further review. Clinician assessment was required to eliminate cases such as parenchymal nervous system or vertebral body metastases, which were not eliminated through the general records search. On occasion, our electronic medical record query flagged imaging reports that stated, “No evidence of leptomeningeal metastasis,” which also had to be eliminated through manual review. Inclusion criteria included histologically confirmed CRC and leptomeningeal disease diagnosed through imaging, pathology, or cytology.1 Exclusion criteria included any noncolorectal primary cancer and any nonleptomeningeal CNS metastasis, such as solitary parenchymal lesions or vertebral body lesions. Patients with parenchymal CNS lesions and leptomeningeal spread were included in the analysis. Demographics, history of the primary CRC, method of LM diagnosis, and history after LM diagnosis were all retrospectively reviewed.
in some cases radiation (Table 1). For those with localized tumors at the time of initial diagnosis, the median time to distant metastasis was 15.5 months (range, 1.5-33 months). In addition to leptomeningeal disease, other sites of metastasis included liver, lung, brain, axial skeleton, and nodal disease. Median overall survival (OS) after diagnosis of CRC was 25.7 months (range, 1-68 months). The median time to diagnosis of LM from the initial diagnosis of CRC was 25.3 months (range, 0-68.1 months). Patients presented with a variety of symptoms, which corresponded to site of the lesions. The most frequent complaints were headache, cranial nerve palsy, vision changes, gait disturbance, and lower extremity weakness (Table 2). All patients were diagnosed with MRI (Table 3). Three patients had cerebrospinal fluid studies; 1 of these was positive for malignant cells, all had elevated protein. Five of the 9 patients had parenchymal brain metastases as well as leptomeningeal disease. Nearly all patients underwent treatment for LM, with 7 of the 9 receiving either targeted spine radiation or whole brain radiation. Three patients received systemic therapy for CRC after diagnosis of LM. No intrathecal chemotherapy was used. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks).
Discussion The diagnosis of LM remains an exceedingly rare occurrence in the natural course of CRC. In their 2004 review of LM cases in gastrointestinal malignancies at MD Anderson between 1944 and 2002, Giglio et al reported 10 cases in 43,761 patients with CRC, a frequency of 0.023%.2 At our institution, the frequency was slightly higher at 10 cases in 17,095 CRC primaries, or 0.058%. Explanations for the higher frequency include better detection methods, with more sensitive MRI capabilities, and longer OS after diagnosis of CRC over the last 20 years, theories also postulated by Yest-Katz, et al in a 2013 series of LM in genitourinary cancers.4,5 Although we did capture cases of LM diagnosed in patients with concurrent parenchymal CNS disease in our series, there remains the possibility that LM is often overlooked, and therefore underdiagnosed, in this situation. From a clinical perspective, we assume more attention is paid to larger, parenchymal lesions when they are present. There are no published recommendations for best treatment of LM arising from colorectal primaries; we are limited to referencing
Results From 17,095 cases of colorectal cancer recorded at our institution between the years of 2000 and 2014, 10 (0.058%) patients with LM were identified. Nine cases were included in the analysis, as the tenth patient presented with an unknown oncologic history and subsequently received care outside of our practice. Of the 9 patients, 5 were female, and the mean age at diagnosis of CRC was 57.1 years (range, 47-63 years). Four patients had metastatic disease at the time of initial CRC diagnosis; 1 of those patients had LM identified on initial staging work-up. Although the ninth patient was still included in our analysis, lung adenocarcinoma was diagnosed on bronchoalveolar lavage at the time of his initial staging. Initial therapies were standard of care treatments, including surgical resection, 5-fluorouracil-based chemotherapy regimens, and
Table 2 Neurologic Symptoms by Site of Leptomeningeal Carcinomatosis Intracranial LM Symptoms (No. of Patients) Cranial nerve palsy (2) Headache (3) Vision changes (2) Seizure (1) Nausea (1) Gait disturbance (1) No apparent symptoms (1)
Spinal LM Symptoms (No. of Patients) Lower extremity weakness (2) Gait disturbance (2) Bowel/bladder incontinence (1) Reduced DTRs (1) Cervical radiculopathy (1) No apparent symptoms (1)
Abbreviations: DTR ¼ deep tendon reflex; LM ¼ leptomeningeal metastasis.
Clinical Colorectal Cancer Month 2017
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Leptomeningeal Carcinomatosis in CRC Table 3 Leptomeningeal Carcinomatosis Course Year LM Patient No. Diagnosed
How Diagnosed
1
2013
MRI
2
2013
MRI
3 4 5
2000 2005 2004
MRI MRI MRI; CSF
6
2005
MRI
7
2006
MRI
8
2005
9
2009
CSF Analysis
LM Site
Neurologic Symptoms
No malignant cells; elevated protein NA
L spine Intracranial
LE weakness; gait disturbance; bladder bowel incontinence CN VI palsy; seizure
NA NA Malignant cells; elevated protein NA
Intracranial C spine Intracranial; T spine L spine
No malignant cells; elevated protein MRI; excisional NA biopsy MRI NA
Intracranial
Headache Cervical radiculopathy CN III palsy; diplopia; ptosis; no T spine symptoms Gait ataxia; LE weakness; reduced DTRs Headache, nausea, facial numbness Headache, gait disturbance
Intracranial
none
Intracranial
Treatment for LM (Concurrent Systemic OS From LM Treatment) Diagnosis, wk RT to L spine; (regorafenib) WBR; (radium 223; FOLFOX ) WBR RT to C spine RT to T spine; WBR
39
4 10 7
None/hospice
2
WBR
6
Lost to follow-up
38
WBR; (FOLFOX þ Avastin)
25
7
Abbreviations: CN ¼ cranial nerve; CSF ¼ cerebrospinal fluid; DTR ¼ deep tendon reflex; FOLFOX ¼ combined 5-fluorouracil, leucovorin, oxaliplatin; LM ¼ leptomeningeal metastasis; MRI ¼ magnetic resonance imaging; NA ¼ not available; OS ¼ overall survival; RT ¼ radiotherapy; WBR ¼ whole brain radiation.
previously published case series and making inferences from therapies used in other primary cancers with leptomeningeal spread. Notably, none of our patients received intrathecal chemotherapy for LM. Recent reviews of treatment strategies in LM arising from solid tumors indicate that intrathecal chemotherapy may not confer a significant survival benefit in relation to unacceptable toxicity e this, in spite of better performance status at baseline allowing candidacy for intrathecal therapy.6 Furthermore, there are no prospective, randomized trials assessing efficacy of systemic versus intrathecal chemotherapy to help guide decision-making for LM in solid tumors. Mack et al, in their 2015 review of LM in solid tumors, suggest reserving intrathecal chemotherapy for cases of diffuse, nonadherent LM only, and using systemic chemotherapy for nodular solid-type LM, with the concern that intrathecal therapy may not reach cells in nodules greater than 2 mm.7 Three patients went on to continue systemic chemotherapy after diagnosis of LM, receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin), regorafenib, and radium-223. None received capecitabine after LM diagnosis, although this has been proposed as an option for CNS and LM metastases in patients with breast cancer.6,8 Recent data emerging in lung cancer suggests that erlotinib can generate a radiologic response in patients with LM, but dosing strategies and conclusive evidence of efficacy in terms of progression-free survival and OS remain elusive.9,10 All but 2 patients in our series received radiation therapy for LM. For those with intracranial LM, whole brain radiation was used; for those with spinal LM, targeted radiotherapy was the chosen modality. Intent was palliative. Patient 2 underwent K-ras mutation testing, which was wild type, and received cetuximab after tumor recurrence. Of the other 8 patients, 6 were deceased before the 2008 landmark article was published by Karapetis et al describing the inactivity of cetruximab in K-ras mutated tumors11; testing was not indicated at the time of their diagnosis. Patient 9 was diagnosed with a concurrent lung adenocarcinoma at the time of his initial staging work-up. Indeed, LM arising from
4
-
Clinical Colorectal Cancer Month 2017
lung cancer primaries is more common, with an estimate of 3% to 5% of nonesmall-cell lung cancer metastasizing to the leptomeninges.12 Given that LM is so rare in CRC, this raises the question of whether a search for second primary neoplasms should be considered when LM is diagnosed in CRC.
Conclusions To our knowledge, this is the single largest published series of cases detailing the clinical course of LM in patients with primary CRC. It remains an exceedingly rare complication of metastatic disease progression in CRC. LM may become more frequently diagnosed as the primary cancer’s survival rates and diagnostic techniques improve. Nevertheless, LM continues to portend a poor prognosis, with median OS after diagnosis only 7 weeks in our series, although one patient had an unusually long survival following the diagnosis. Irinotecan and capecitabine have not been studied as therapy for CRC LM and can be considered given their ability to cross the blood-brain barrier if not previously used. Radiation therapy can be considered in symptomatic patients, but its role in prolonging survival has not been proven. Based on our analysis, supportive care remains a sensible option the management of LM in CRC.
Clinical Practice Points Leptomeningeal carcinomatosis is a rare metastatic progression of
primary CRC. An LM diagnosis portends a poor prognosis, with median OS 7
weeks in our series. Most patients in our series received radiation therapy in the form
of whole-brain or targeted spine radiation in a palliative approach.
Disclosure The authors have stated that they have no conflicts of interest.
Gretchen Taylor et al References 1. Grossman S, Krabak M. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999; 25:103-19. 2. Giglio P, Weinberg JS, Forman AD, Wolff R, Groves MD. Neoplastic meningitis in patients with adenocarcinoma of the gastrointestinal tract. Cancer 2005; 103:2355-62. 3. Shah L, Salzman K. Imaging of spinal metastatic disease. Int J Surg Oncol 2011; 2011:769753. 4. Kemeny N. Treatment of metastatic colon cancer: “the times they are a-changing”. J Clin Oncol 2013; 31:1913-6. 5. Yust-Katz S, Mathis S, Groves M. Leptomeningeal metastases from genitourinary cancer: the University of Texas MD Anderson Cancer Center experience. Med Oncol 2013; 30:429. 6. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: leptomeningeal metastases in solid tumors. Surg Neurol Int 2013; 4:S265-88.
7. Mack F, Baumert BG, Schafer N, et al. Therapy of leptomeningeal metastasis in solid tumors. Cancer Treat Rev 2016; 43:83-91. 8. Ekenel M, Hormigo AM, Peak S, et al. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007; 85:223-7. 9. Kuiper JL, Hendriks LE, van der Wekken AJ, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer 2015; 89:255-61. 10. Wagner M, Besse B, Balleyguier C, Soria J-C. Leptomeningeal and medullary response to second-line erlotinib in lung adenocarcinoma. J Thorac Oncol 2008; 3: 677-9. 11. Karapetis C, Khambata-Ford S, Jonker D, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65. 12. Riess J, Nagpal S, Iv M, et al. Prolonged survival of patients with NSCLC with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung Cancer 2014; 15:202-6.
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Leptomeningeal Carcinomatosis in Colorectal Cancer: The Mayo Clinic Experience Gretchen Taylor,1 Nina Karlin,2 Thorvardur R. Halfdanarson,3 Kyle Coppola,2 Axel Grothey3 Abstract Leptomeningeal carcinomatosis is an uncommon metastatic progression of colorectal cancer. A database search of 17,095 primary colorectal cancers in a 15-year period returned 10 cases of leptomeningeal metastasis in these patients. Our series describes their disease course and outcomes. Leptomeningeal carcinomatosis confers a poor prognosis, with most patients receiving palliative therapies after the diagnosis was made. Background: Leptomeningeal metastasis (LM) is an uncommon form of metastatic disease in many cancers. There remains a paucity of literature with regard to the course and management of LM in colorectal cancers (CRCs). The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. Median overall survival after CRC diagnosis was 25.7 months (range, 4.7-74.8 months). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range, 0-68.1 months). All patients had magnetic resonance imaging findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, and 1 with both. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in 2 cases. Seven patients (78%) had palliative radiotherapy for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks). Conclusions: LM is an exceedingly rare development in the natural course of CRC. It confers a poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving radiotherapy to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Gastrointestinal, Neoplastic meningitis, Nervous system metastases, Oncology, Rare
Introduction Leptomeningeal carcinomatosis (LM), or neoplastic meningitis, is an uncommon metastatic complication of solid tumor progression. Most commonly arising from breast, nonesmall-cell lung cancer, and melanoma with a frequency of 5% to 25%,1 its incidence in colorectal 1
Department of Internal Medicine, Mayo Clinic Arizona, Scottsdale, AZ Division of Hematology-Oncology, Mayo Clinic Arizona, Phoenix, AZ 3 Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN 2
cancer (CRC) is far less than 1%.2 Suspicion for central nervous system (CNS) metastasis is raised when a patient presents with new neurologic complaints in the setting of a metastatic cancer. Gadoliniumenhanced T1-weighted magnetic resonance imaging (MRI) remains the most sensitive imaging diagnostic tool, with LM defined by abnormal leptomeningeal enhancement or small subarachnoid nodules.3 The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases.
Submitted: Aug 25, 2017; Revised: Oct 19, 2017; Accepted: Nov 14, 2017 Address for correspondence: Gretchen Taylor, MD, Department of Internal Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clcc.2017.11.003
Methods Institutional review board approval and waiver of consent were granted for an electronic medical records search. The Cancer
Clinical Colorectal Cancer Month 2017
-1
2
Gender
Year of Primary Diagnosis
1
F
2008
2
M
2007
3
F
2000
4
F
2001
5
M
2003
6
F
2003
7
M
8
9a
Patient
TNM Stage at Diagnosis
Treatment of Primary Cancer
Adenocarcinoma, moderately differentiated Adenocarcinoma with signet ring cell features; invasive, grade 3-4
T3N0M0
Resection; 5-FU; FOLFOX; capecitabine Resection; FOLFOX; 5-FU
Adenocarcinoma invasive, grade 3 Mucinous adenocarcinoma invasive, grade 2 Mucinous adenocarcinoma invasive, grade 3
TxNxM1
Pathologic Type
T3N0M0
Time to Metastasis, wk 88 133
T3N1M0
Resection (palliative); 5-FU; CPT-11 Resection; CPT-11, oxaliplatin Resection
6
Mucinous adenocarcinoma, grade 2
T3N1M0
Resection; 5-FU
56
2006
Adenocarcinoma invasive, grade 4
TxN1Mx
RT, 5-FU
0
F
2002
Adenocarcinoma invasive, grade 2
T3NxMx
Neo-adj RT, 5-FU; resection
26
M
2009
Adenocarcinoma invasive, poorly differentiated
TxNxM1
WBR, RT; FOLFOX þ Avastin
3
T2N2Mx
0 0
Treatment of Recurrence
Sites of Metastases
Year LM Diagnosed
Time to LM From Initial Diagnosis, mo
FOLFIRI þ Avastin; regorafenib Resection (liver); FOLFOX; capecitabine; RT; FOLFIRI þ bevacizumab; capecitabine þ bevacizumab; CPT-11 þ cetuximab; regorafenib; Rad-223 N/A
Liver, lung
2013
65.7
Liver, vertebra
2013
68.1
Liver, lung
2000
8.7
Liver, mediastinum, brain Nodal (supraclavicular, periaortic), axial skeleton, brain Liver, brain
2005
48.3
2004
6.7
2005
25.3
Nodal (pelvic, retroperitoneal, supraclavicular, subcarinal) Brain
2006
3.4
2005
36.7
2009
0
Resections (mediastinum, brain); WBR 5-FU, oxaliplatin; WBR
Resection (liver); FOLFOX, Avastin; CPT-11; resection (brain); WBR N/A
Resection (brain); WBR; Xeloda; RT; CPT-11; resection (brain, 2nd and 3rd) N/A
Axial skeleton, adrenal, brain
Abbreviations: CPT-11 ¼ irinotecan; F ¼ female; FOLFIRI ¼ combined 5-FU, leucovorin, irinotecan; FOLFOX ¼ combined 5-FU, leucovorin, oxaliplatin; 5-FU ¼ 5-fluorouracil; LM ¼ leptomeningeal metastasis; M ¼ male; RT ¼ radiotherapy; WBR ¼ whole brain radiation. a Patient No. 9: Concurrent lung adenocarcinoma found on bronchoalveolar lavage at time of initial work-up.
Leptomeningeal Carcinomatosis in CRC
Clinical Colorectal Cancer Month 2017
Table 1 Primary Colorectal Cancer History
Gretchen Taylor et al Registry identified all CRC primaries diagnosed between the years of 2000 and 2014 at our institution. The medical record numbers of these cases were then sent to 2 institutional data groups with a request to identify the concurrent diagnosis of LM. First, International Classification of Diseases, Ninth Revision code searches for “198.4: secondary malignant neoplasm of other parts of the nervous system” and “349.2: disorders of meninges, not elsewhere classified” was undertaken. The second data group was tasked with a term search within the medical records of these patients with CRC. They queried cytology reports of cerebral spinal fluid analysis for the terms “leptomeningeal carcinomatosis,” “carcinomatous meningitis,” “neoplastic meningitis,” “leptomeningeal cancer,” “leptomeningeal metastasis,” “leptomeningeal carcinoma,” and “meningeal metastasis.” In addition, all biopsies of a CNS mass in a patient with CRC were identified, and those pathology cases were flagged for further review if the report included the term “metastatic.” The data group also queried the electronic database for imaging reports of the brain, head, spine, vertebra, and sinuses (MRI, magnetic resonance angiography, computed tomography, positron emission technology) for the terms “leptomeningeal” or “leptomeninges” in the cases of patients with CRC. The medical record review yielded 93 unique cases, which were sent to the research clinicians for further review. Of these cases, 64 had a billing diagnosis of either 198.4 or 349.2. Of the 93, there were 29 unique cases with an imaging report flagged for further review. Clinician assessment was required to eliminate cases such as parenchymal nervous system or vertebral body metastases, which were not eliminated through the general records search. On occasion, our electronic medical record query flagged imaging reports that stated, “No evidence of leptomeningeal metastasis,” which also had to be eliminated through manual review. Inclusion criteria included histologically confirmed CRC and leptomeningeal disease diagnosed through imaging, pathology, or cytology.1 Exclusion criteria included any noncolorectal primary cancer and any nonleptomeningeal CNS metastasis, such as solitary parenchymal lesions or vertebral body lesions. Patients with parenchymal CNS lesions and leptomeningeal spread were included in the analysis. Demographics, history of the primary CRC, method of LM diagnosis, and history after LM diagnosis were all retrospectively reviewed.
in some cases radiation (Table 1). For those with localized tumors at the time of initial diagnosis, the median time to distant metastasis was 15.5 months (range, 1.5-33 months). In addition to leptomeningeal disease, other sites of metastasis included liver, lung, brain, axial skeleton, and nodal disease. Median overall survival (OS) after diagnosis of CRC was 25.7 months (range, 1-68 months). The median time to diagnosis of LM from the initial diagnosis of CRC was 25.3 months (range, 0-68.1 months). Patients presented with a variety of symptoms, which corresponded to site of the lesions. The most frequent complaints were headache, cranial nerve palsy, vision changes, gait disturbance, and lower extremity weakness (Table 2). All patients were diagnosed with MRI (Table 3). Three patients had cerebrospinal fluid studies; 1 of these was positive for malignant cells, all had elevated protein. Five of the 9 patients had parenchymal brain metastases as well as leptomeningeal disease. Nearly all patients underwent treatment for LM, with 7 of the 9 receiving either targeted spine radiation or whole brain radiation. Three patients received systemic therapy for CRC after diagnosis of LM. No intrathecal chemotherapy was used. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks).
Discussion The diagnosis of LM remains an exceedingly rare occurrence in the natural course of CRC. In their 2004 review of LM cases in gastrointestinal malignancies at MD Anderson between 1944 and 2002, Giglio et al reported 10 cases in 43,761 patients with CRC, a frequency of 0.023%.2 At our institution, the frequency was slightly higher at 10 cases in 17,095 CRC primaries, or 0.058%. Explanations for the higher frequency include better detection methods, with more sensitive MRI capabilities, and longer OS after diagnosis of CRC over the last 20 years, theories also postulated by Yest-Katz, et al in a 2013 series of LM in genitourinary cancers.4,5 Although we did capture cases of LM diagnosed in patients with concurrent parenchymal CNS disease in our series, there remains the possibility that LM is often overlooked, and therefore underdiagnosed, in this situation. From a clinical perspective, we assume more attention is paid to larger, parenchymal lesions when they are present. There are no published recommendations for best treatment of LM arising from colorectal primaries; we are limited to referencing
Results From 17,095 cases of colorectal cancer recorded at our institution between the years of 2000 and 2014, 10 (0.058%) patients with LM were identified. Nine cases were included in the analysis, as the tenth patient presented with an unknown oncologic history and subsequently received care outside of our practice. Of the 9 patients, 5 were female, and the mean age at diagnosis of CRC was 57.1 years (range, 47-63 years). Four patients had metastatic disease at the time of initial CRC diagnosis; 1 of those patients had LM identified on initial staging work-up. Although the ninth patient was still included in our analysis, lung adenocarcinoma was diagnosed on bronchoalveolar lavage at the time of his initial staging. Initial therapies were standard of care treatments, including surgical resection, 5-fluorouracil-based chemotherapy regimens, and
Table 2 Neurologic Symptoms by Site of Leptomeningeal Carcinomatosis Intracranial LM Symptoms (No. of Patients) Cranial nerve palsy (2) Headache (3) Vision changes (2) Seizure (1) Nausea (1) Gait disturbance (1) No apparent symptoms (1)
Spinal LM Symptoms (No. of Patients) Lower extremity weakness (2) Gait disturbance (2) Bowel/bladder incontinence (1) Reduced DTRs (1) Cervical radiculopathy (1) No apparent symptoms (1)
Abbreviations: DTR ¼ deep tendon reflex; LM ¼ leptomeningeal metastasis.
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Leptomeningeal Carcinomatosis in CRC Table 3 Leptomeningeal Carcinomatosis Course Year LM Patient No. Diagnosed
How Diagnosed
1
2013
MRI
2
2013
MRI
3 4 5
2000 2005 2004
MRI MRI MRI; CSF
6
2005
MRI
7
2006
MRI
8
2005
9
2009
CSF Analysis
LM Site
Neurologic Symptoms
No malignant cells; elevated protein NA
L spine Intracranial
LE weakness; gait disturbance; bladder bowel incontinence CN VI palsy; seizure
NA NA Malignant cells; elevated protein NA
Intracranial C spine Intracranial; T spine L spine
No malignant cells; elevated protein MRI; excisional NA biopsy MRI NA
Intracranial
Headache Cervical radiculopathy CN III palsy; diplopia; ptosis; no T spine symptoms Gait ataxia; LE weakness; reduced DTRs Headache, nausea, facial numbness Headache, gait disturbance
Intracranial
none
Intracranial
Treatment for LM (Concurrent Systemic OS From LM Treatment) Diagnosis, wk RT to L spine; (regorafenib) WBR; (radium 223; FOLFOX ) WBR RT to C spine RT to T spine; WBR
39
4 10 7
None/hospice
2
WBR
6
Lost to follow-up
38
WBR; (FOLFOX þ Avastin)
25
7
Abbreviations: CN ¼ cranial nerve; CSF ¼ cerebrospinal fluid; DTR ¼ deep tendon reflex; FOLFOX ¼ combined 5-fluorouracil, leucovorin, oxaliplatin; LM ¼ leptomeningeal metastasis; MRI ¼ magnetic resonance imaging; NA ¼ not available; OS ¼ overall survival; RT ¼ radiotherapy; WBR ¼ whole brain radiation.
previously published case series and making inferences from therapies used in other primary cancers with leptomeningeal spread. Notably, none of our patients received intrathecal chemotherapy for LM. Recent reviews of treatment strategies in LM arising from solid tumors indicate that intrathecal chemotherapy may not confer a significant survival benefit in relation to unacceptable toxicity e this, in spite of better performance status at baseline allowing candidacy for intrathecal therapy.6 Furthermore, there are no prospective, randomized trials assessing efficacy of systemic versus intrathecal chemotherapy to help guide decision-making for LM in solid tumors. Mack et al, in their 2015 review of LM in solid tumors, suggest reserving intrathecal chemotherapy for cases of diffuse, nonadherent LM only, and using systemic chemotherapy for nodular solid-type LM, with the concern that intrathecal therapy may not reach cells in nodules greater than 2 mm.7 Three patients went on to continue systemic chemotherapy after diagnosis of LM, receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin), regorafenib, and radium-223. None received capecitabine after LM diagnosis, although this has been proposed as an option for CNS and LM metastases in patients with breast cancer.6,8 Recent data emerging in lung cancer suggests that erlotinib can generate a radiologic response in patients with LM, but dosing strategies and conclusive evidence of efficacy in terms of progression-free survival and OS remain elusive.9,10 All but 2 patients in our series received radiation therapy for LM. For those with intracranial LM, whole brain radiation was used; for those with spinal LM, targeted radiotherapy was the chosen modality. Intent was palliative. Patient 2 underwent K-ras mutation testing, which was wild type, and received cetuximab after tumor recurrence. Of the other 8 patients, 6 were deceased before the 2008 landmark article was published by Karapetis et al describing the inactivity of cetruximab in K-ras mutated tumors11; testing was not indicated at the time of their diagnosis. Patient 9 was diagnosed with a concurrent lung adenocarcinoma at the time of his initial staging work-up. Indeed, LM arising from
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lung cancer primaries is more common, with an estimate of 3% to 5% of nonesmall-cell lung cancer metastasizing to the leptomeninges.12 Given that LM is so rare in CRC, this raises the question of whether a search for second primary neoplasms should be considered when LM is diagnosed in CRC.
Conclusions To our knowledge, this is the single largest published series of cases detailing the clinical course of LM in patients with primary CRC. It remains an exceedingly rare complication of metastatic disease progression in CRC. LM may become more frequently diagnosed as the primary cancer’s survival rates and diagnostic techniques improve. Nevertheless, LM continues to portend a poor prognosis, with median OS after diagnosis only 7 weeks in our series, although one patient had an unusually long survival following the diagnosis. Irinotecan and capecitabine have not been studied as therapy for CRC LM and can be considered given their ability to cross the blood-brain barrier if not previously used. Radiation therapy can be considered in symptomatic patients, but its role in prolonging survival has not been proven. Based on our analysis, supportive care remains a sensible option the management of LM in CRC.
Clinical Practice Points Leptomeningeal carcinomatosis is a rare metastatic progression of
primary CRC. An LM diagnosis portends a poor prognosis, with median OS 7
weeks in our series. Most patients in our series received radiation therapy in the form
of whole-brain or targeted spine radiation in a palliative approach.
Disclosure The authors have stated that they have no conflicts of interest.
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7. Mack F, Baumert BG, Schafer N, et al. Therapy of leptomeningeal metastasis in solid tumors. Cancer Treat Rev 2016; 43:83-91. 8. Ekenel M, Hormigo AM, Peak S, et al. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007; 85:223-7. 9. Kuiper JL, Hendriks LE, van der Wekken AJ, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer 2015; 89:255-61. 10. Wagner M, Besse B, Balleyguier C, Soria J-C. Leptomeningeal and medullary response to second-line erlotinib in lung adenocarcinoma. J Thorac Oncol 2008; 3: 677-9. 11. Karapetis C, Khambata-Ford S, Jonker D, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65. 12. Riess J, Nagpal S, Iv M, et al. Prolonged survival of patients with NSCLC with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung Cancer 2014; 15:202-6.
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