HEMONC 306 No.

of Pages 5, Model 6+
17 October 2019
Hematol Oncol Stem Cell Ther xxx (xxxx) xxx
1

Available at www.sciencedirect.com

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journal homepage: www.elsevier.com/locate/hemonc

2 ORIGINAL RESEARCH REPORT

8
9
4 High-dose intravenous methotrexate in the
5 management of breast cancer with
6 leptomeningeal disease: Case series and
7 review of the literature
10 Jonathan T. Kapke a,*, Robert J. Schneidewend a, Zeeshan A. Jawa a
11 Chiang-Ching Huang b, Jennifer M. Connelly a, Christopher R. Chitambar a

a
12 Medical College of Wisconsin, Milwaukee, WI, USA
b
13 University of Wisconsin–Milwaukee, Milwaukee, WI, USA

14 Received 7 October 2018; received in revised form 25 June 2019; accepted 30 August 2019
15

25
26
17
27 KEYWORDS Abstract
18
28 Metastatic breast cancer; Leptomeningeal metastasis (LM) in breast cancer is associated with significant morbidity and
19 Leptomeningeal carcino-
29 mortality. While there is currently no standard therapy, treatment options include craniospinal
20 matosis;
30 radiotherapy, intrathecal chemotherapy and systemic chemotherapy. Craniospinal radiother-
21 Leptomeningeal disease;
31
22 High dose methotrexate; apy has not demonstrated improved survival and intrathecal chemotherapy is often poorly tol-
32
23 Intrathecal chemotherapy; erated due to associated neurotoxicity. The use of systemic chemotherapy can be limited by
33
24 Craniospinal radiotherapy inadequate central nervous system penetration. High-dose systemic methotrexate adminis-
34 tered intravenously (HD-MTX), has been reported to improve quality of life and provide durable
35 remissions for LM in breast cancer. We present three cases of metastatic breast cancer and LM
36 with prolonged survival after administration of HD-MTX. Based on our observations and review
37 of the literature, HD-MTX seems to be a viable treatment option for patients with LM in breast
38 cancer, and in select cases, the use of HD-MTX, as part of a multimodality treatment plan, may
39 be associated with prolonged survival.
44
41
40 Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an
42 open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
43 nd/4.0/).

* Corresponding author at: Division of Hematology and Oncology, Medical College of Wisconsin and Froedtert Clinical Cancer Center,
Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA. Fax: 414-805-4606.
E-mail address: jt.kapke@gmail.com (J.T. Kapke).

https://doi.org/10.1016/j.hemonc.2019.08.008
1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: J. T. Kapke, R. J. Schneidewend, Z. A. Jawa et al., High-dose intravenous methotrexate in the management of breast
cancer with leptomeningeal disease: Case series and review of the literature, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.

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 HEMONC 306 No. of Pages 5, Model 6+
17 October 2019
2 J.T. Kapke et al.

45 Introduction the cervical and lumbar spine, as well as, extensive lep- 101
tomeningeal carcinomatosis. Of note, MRI brain was nega- 102
tive for parenchymal brain lesions. Initial staging 103
46 Breast cancer is the most common malignancy among
computed tomography (CT) demonstrated a large lobulated 104
47 females worldwide, and in the USA, it affects approximately
enhancing heterogeneous left breast mass, measuring 105
48 one in eight women [1,2]. Breast cancer commonly spreads
approximately 3.2  3.2 cm, with left axillary lym- 106
49 to the central nervous system (CNS), and when compared to
phadenopathy. The patient underwent a left breast biopsy 107
50 other solid tumor malignancies, only lung cancer is more
with pathology significant for invasive ductal carcinoma that 108
51 commonly associated with CNS metastasis [3]. Lep-
was estrogen receptor (ER)-positive, progesterone receptor 109
52 tomeningeal metastasis (LM), where deposits of malignant
(PR)-positive, and HER2-negative. She underwent lumbar 110
53 cells occupy the lining of the CNS, has an estimated inci-
puncture with cerebrospinal fluid (CSF) cytology analysis 111
54 dence of less than 5% in metastatic breast cancer and is
positive for metastatic breast cancer. The patient was 112
55 associated with significant morbidity and mortality [4]. Risk
started on dexamethasone and treated with palliative radi- 113
56 factors for developing LM include triple-negative and human
ation therapy to the cervical and lumbar spine. Her lower 114
57 epidermal growth factor receptor 2 (HER-2) positive dis-
extremity strength improved, and she was discharged home. 115
58 ease, as well as invasive lobular histology [5,6]. Estimated
The patient subsequently received systemic chemother- 116
59 survival after diagnosis of LM ranges from 6 to 8 weeks in
apy using intravenous HD-MTX with leucovorin rescue until 117
60 those left untreated to 8–30 weeks in those who receive
plasma methotrexate levels were <0.1 µM. She received a 118
61 therapy, and in general, less than 10–20% of breast cancer
total of seven cycles of therapy, and treatment was repeated 119
62 patients live more than 1 year after LM diagnosis [7,8].
every 14 days. Cycle one was dosed at 3.5 g/m2, cycle two 120
63 There is no standard treatment for LM in breast cancer.
was dosed at 4 g/m2, and cycles three to seven were dosed 121
64 Current treatment options include craniospinal radiother-
at 8 g/m2. Anastrozole 1 mg daily was added with cycle 122
65 apy, intrathecal chemotherapy, and systemic chemother-
seven. Treatment was tolerated relatively well without sig- 123
66 apy. Although radiotherapy seems to alleviate signs and
nificant complications. After completing seven cycles of 124
67 symptoms of LM, it has not been shown to prolong survival
therapy, the patient’s palpable breast mass dramatically 125
68 [8,9]. In addition, although commonly used in clinical prac-
decreased in size with only a 1-cm scar remaining on physical 126
69 tice, the efficacy of intrathecal chemotherapy is not well
exam, and CSF cytology became negative for malignancy. 127
70 established, and it is often poorly tolerated because of sig-
Restaging imaging demonstrated improvement in epidural 128
71 nificant neurotoxicity [10]. Data supporting the use of sys-
soft tissue enhancement, regression of spinal metastatic dis- 129
72 temic chemotherapy for LM are limited to case reports
ease, and decreasing leptomeningeal carcinomatosis. 130
73 and small case series as most patients with LM are excluded
It was felt that the patient had achieved a maximum ben- 131
74 from larger clinical trials. Observed efficacy has been seen
efit after seven cycles of HD-MTX, and the decision was 132
75 in a limited number of regimens that have adequate CNS
made to transition to capecitabine. The patient was main- 133
76 penetration. High-dose intravenous methotrexate (HD-
tained on capecitabine for approximately 18 months, but 134
77 MTX) has been shown in retrospective studies and case
then she developed posterior reversible encephalopathy 135
78 reports to have significant efficacy when compared to other
syndrome that was attributed to capecitabine as her symp- 136
79 therapies for patients with LM [10–12].
toms resolved with drug discontinuation. She was continued 137
80 Methotrexate is a folate antimetabolite that inhibits DNA
on anastrozole alone for 7 months until restaging imaging 138
81 synthesis, repair, and cellular replication. When dosed at
demonstrated worsening osseous metastasis and new pul- 139
82 3.5–16 g/m2, HD-MTX has been shown to achieve CNS drug
monary nodules consistent with progressive metastatic dis- 140
83 levels necessary for antitumor effect [11,13]. The use of
ease. Palbociclib was added to anastrozole for about 141
84 HD-MTX has been well established for prophylaxis and treat-
5 months, but the patient developed altered mental status, 142
85 ment of CNS disease in lymphoma and leukemia. Although
and restaging MRI demonstrated an enlarging left parasagit- 143
86 there are less data on its use for leptomeningeal carcino-
tal falx lesion with stable leptomeningeal disease. Anastro- 144
87 matosis in solid tumor malignancies, HD-MTX has been
zole was switched to exemestane and palbociclib was 145
88 reported to improve quality of life and provide disease
continued for several months. The patient then developed 146
89 remissions far beyond the estimated averages for breast
progressive pulmonary, hepatic, and CNS disease and subse- 147
90 cancer patients with LM [7,12,14,15].
quently transitioned to abemaciclib plus fulvestrant. While 148
91 We present three cases of metastatic breast cancer with
on abemaciclib, the patient experienced progressive diar- 149
92 LM that achieved prolonged survival after treatment with
rhea that was difficult to control. She ultimately elected 150
93 HD-MTX and provide a review of the literature.
to stop this agent for quality of life reasons after being on 151
treatment for approximately 7 months. Fulvestrant was 152

94 Case reports continued alone for 7 additional months. Restaging imaging 153
then demonstrated progressive disease in the liver, but 154
stable osseous, CNS, and leptomeningeal disease. The 155
95 Case 1
patient was started on paclitaxel chemotherapy, which 156
she continues to date. 157
96 LH is a 71-year-old female with a history of ulcerative colitis At the time of this writing, the patient is alive and toler- 158
97 who initially presented in December 2014 with progressive ating systemic therapy without significant dose limiting tox- 159
98 lower extremity weakness. She was admitted for further icity. Her leptomeningeal disease is radiographically and 160
99 management and magnetic resonance imaging (MRI) of the clinically stable. Despite being diagnosed with lep- 161
100 spine showed multiple focal metastatic lesions throughout tomeningeal disease at initial presentation, the patient 162

Please cite this article as: J. T. Kapke, R. J. Schneidewend, Z. A. Jawa et al., High-dose intravenous methotrexate in the management of breast
cancer with leptomeningeal disease: Case series and review of the literature, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.

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 HEMONC 306 No. of Pages 5, Model 6+
17 October 2019
High-dose intravenous methotrexate in the management of breast cancer 3

163 has survived 54 months with systemic therapy, including In October 2013, restaging PET/CT demonstrated exten- 220
164 first line HD-MTX, and she has maintained an excellent qual- sive progression of disease within the liver, bones, and 221
165 ity of life. lungs. Worsening leptomeningeal disease was also seen, 222
but no parenchymal brain lesions were observed. It was at 223
166 Case 2 that time that she elected to transfer her care to our insti- 224
tution. Liver biopsy was performed with pathology positive 225

167 MY is a 63-year-old female who was initially diagnosed with for metastatic breast cancer that was ER-positive, PR- 226

168 left breast cancer in May 2006. She was treated with left positive, and HER2-negative. Reassessment of menopausal 227

169 mastectomy and bilateral salpingo-oophorectomy. Final status with laboratory testing demonstrated a pre- 228

170 pathology demonstrated stage IIA, T2N0 invasive lobular menopausal state. Ovarian function suppression with 229

171 carcinoma, ER-positive, PR-positive, HER2-negative. She leuprolide was added to anastrozole, and palliative radia- 230

172 was subsequently treated with six cycles of docetaxel, dox- tion therapy to the whole brain and to an L5 compression 231

173 orubicin, and cyclophosphamide (TAC) chemotherapy fol- fracture was administered. 232

174 lowed by adjuvant radiation. She was offered adjuvant The patient subsequently received weekly paclitaxel and 233

175 hormone therapy but declined treatment at that time. bevacizumab, administered on Day 1 and Day 15 of a 21-day 234

176 The patient was in remission until July 2015, when she cycle, for a total of three cycles. Restaging imaging demon- 235

177 presented with progressive weakness and vision changes. strated disease progression in the liver, and treatment was 236

178 Restaging imaging demonstrated leptomeningeal carcino- switched to eribulin administered on Day 1 and Day 8 of a 237

179 matosis with associated optic nerve compression, patho- 21-day cycle. She received eight cycles of eribulin, and then 238

180 logic L5 compression fracture, and extensive bony disease. elected to take a treatment break for bilateral salpingo- 239

181 The patient underwent L5 laminectomy. Surgical pathology opherectomy. Anastrozole was changed to letrozole. 240

182 was positive for metastatic invasive lobular carcinoma of Restaging scans 5 months later demonstrated progressive 241

183 the breast, ER-positive, PR-positive, and HER2-negative. disease in the liver and bone. She resumed eribulin for an 242

184 She was started on anastrozole and subsequently received additional six cycles. Restaging imaging in March 2015 243

185 six cycles of HD-MTX at a dose of 8 g/m2, which was com- demonstrated disease progression in the liver and bone, as 244

186 pleted in October 2015. Restaging imaging at that time well as progressive leptomeningeal carcinomatosis. 245

187 demonstrated regression of leptomeningeal carcinomatosis In light of significant worsening leptomeningeal disease, 246

188 and bony disease. She was subsequently started on palboci- the patient received five cycles of with HD-MTX dosed at 247

189 clib and letrozole. 8 g/m2. Restaging imaging demonstrated stable lep- 248

190 At the time of this writing, the patient is alive and well. tomeningeal disease, but disease progression in the liver. 249

191 She remains on palbociclib and letrozole without dose limit- She was then treated with carboplatin and gemcitabine 250

192 ing toxicity. Her leptomeningeal disease remains stable, and for three cycles with stable leptomeningeal disease but 251

193 to date the patient’s disease has been controlled for ongoing progression in the liver. Treatment was changed 252

194 44 months since the initial diagnosis of leptomeningeal to capecitabine. After six cycles of capecitabine, oligome- 253

195 carcinomatosis. tastatic progression of disease was noted in the thoracic 254
spine. The patient received palliative radiation therapy to 255

196 Case 3 the thoracic lesion, and capecitabine was administered for 256
three more cycles. Restaging imaging subsequently demon- 257
strated stable leptomeningeal disease; however, significant 258
197 CB is a 45-year-old female who was diagnosed with right
progression was noted in the liver and throughout the skele- 259
198 breast cancer in 2010. Initial treatment included lumpec-
ton. The patient transitioned to end-of-life care and died in 260
199 tomy plus sentinel lymph node biopsy. Pathology demon-
August 2016. The patient lived a total of 17 months after the 261
200 strated a 2.0-cm invasive ductal carcinoma with negative
initial diagnosis of leptomeningeal disease. 262
201 sentinel lymph node sampling, ER-positive, PR-positive,
202 HER2-negative. The Oncotype DX Recurrence Score was
203 30. She subsequently received four cycles of dose-dense Discussion 263

204 doxorubicin and cyclophosphamide (DDAC) followed by

205 postoperative radiation therapy. The patient started tamox- Treatment of metastatic breast cancer with LM remains a 264
206 ifen after completing radiation in March 2011. significant therapeutic challenge. Prognosis is very poor, 265
207 In September 2013, the patient presented with progres- and there are no standard treatments. Potential treatment 266
208 sive hip pain and headaches. She underwent a positron options include radiotherapy, intrathecal chemotherapy, 267
209 emission tomography (PET)/CT that demonstrated a bilobed and systemic chemotherapy, but limited data are available 268
210 suprahilar right-sided mass measuring 1.7  1.2 cm, as well to guide optimal treatment selection [16]. 269
211 as, a lytic lesion in L5 and the right iliac wing. Biopsy of the Available data suggests that radiation therapy for LM is 270
212 right iliac wing lesion demonstrated metastatic breast can- often associated with an initial improvement in neurologic 271
213 cer, ER-positive, PR-positive, and HER2-negative. MRI of the signs and symptoms; however, the clinical improvement 272
214 brain demonstrated dural enhancement highly suspicious for from radiation therapy is often short-lived [8,9,17]. Fur- 273
215 leptomeningeal carcinomatosis without parenchymal brain thermore, despite the symptomatic improvement, radiation 274
216 metastasis. Of note, the patient had been amenorrhoeic therapy for LM in breast cancer has not been associated with 275
217 since receiving chemotherapy 2 years earlier, and labora- an overall survival benefit [8]. Craniospinal and whole brain 276
218 tory assessment suggested menopausal status. She was radiation therapy have also been associated with a variety 277
219 started on anastrozole 1 mg daily in July 2013. of neurocognitive side effects that may significantly impact 278

Please cite this article as: J. T. Kapke, R. J. Schneidewend, Z. A. Jawa et al., High-dose intravenous methotrexate in the management of breast
cancer with leptomeningeal disease: Case series and review of the literature, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.

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 HEMONC 306 No. of Pages 5, Model 6+
17 October 2019
4 J.T. Kapke et al.

279 quality of life, particularly in patients who achieve a rela- Glantz et al. [12] reported on 16 patients with solid 341
280 tively long-term survival with LM [18]. Finally, the use of tumor LM who were treated with HD-MTX dosed at 8 g/m2. 342
281 craniospinal and whole brain radiotherapy may decrease Toxicity, response, and survival were compared to a refer- 343
282 the ability for systemic therapy to penetrate the blood– ence group of 15 patients who received standard intrathecal 344
283 brain barrier and potentially limit the effect of systemic methotrexate. The median overall survival for those who 345
284 therapy on the management of LM. received HD-MTX was 13.8 months compared to 2.3 months 346
285 Although commonly used in clinical practice, the efficacy for the intrathecal methotrexate group (p = .003) [12]. The 347
286 of intrathecal chemotherapy is not well established, and it toxicity of the HD-MTX was minimal, and adequate CSF drug 348
287 is often poorly tolerated because of significant neurotoxic- concentrations were measured. This study supports the use 349
288 ity [10]. Commonly used intrathecal agents for the treat- of HD-MTX as a viable treatment option for LM in metastatic 350
289 ment of LM include methotrexate, cytarabine, and solid tumors including breast cancer; the survival observa- 351
290 thiotepa. Intrathecal chemotherapy administration typically tions suggest superiority of this therapy to intrathecal 352
291 requires frequent lumbar punctures, which often adds addi- chemotherapy. 353
292 tional logistical challenges and exposes the patient to addi- Researchers have also studied the combination of HD- 354
293 tional procedure related risks. Various studies have MTX with intrathecal chemotherapy. In a Phase II study by 355
294 evaluated intrathecal chemotherapy for LM with disappoint- Mrugala et al. [20] that closed early because of poor accrual, 356
295 ing results. patients with breast cancer and LM were treated with HD- 357
296 In a study by Niwinska et al., outcomes were measured MTX in combination with intrathecal liposomal cytarabine. 358
297 for 149 patients with breast cancer and LM who received a The three patients reported in this study had an overall sur- 359
298 variety of treatment modalities. In addition, the efficacy vival of 11.3, 8.2, and 5.5 months at time of data extraction 360
299 of intrathecal methotrexate was compared to intrathecal [20]. The small sample size makes it difficult to interpret 361
300 liposomal cytarabine. Median survival from LM diagnosis these data; however, the reported survival does suggest that 362
301 for study patients receiving intrathecal methotrexate was HD-MTX with or without intrathecal chemotherapy may be a 363
302 4.2 months compared to 4.6 months for those receiving viable option for LM in breast cancer. 364
303 intrathecal liposomal cytarabine. The study concluded that Overall, the data reviewed, including our report, suggest 365
304 intrathecal chemotherapy was not associated with an over- that HD-MTX is a viable treatment option for LM in breast 366
305 all survival benefit. Significant neurologic toxicities were cancer. Our observations suggest that integrating HD-MTX 367
306 observed for patients receiving intrathecal chemotherapy. into a multimodality treatment plan can be associated with 368
307 Specifically, 47% of patients receiving intrathecal prolonged survival in select cases of breast cancer with LM. 369
308 chemotherapy had neurologic complications compared to Currently, there are limited data available to help predict 370
309 only 6% in patients who did not receive intrathecal which patients with LM might respond to therapy. Further 371
310 chemotherapy (p = .007). Finally, in a planned analysis of study is necessary to better understand the underlying phar- 372
311 the effect of radiation therapy and systemic therapy on sur- macogenomics of responders compared to nonresponders to 373
312 vival, only systemic therapy was associated with an better guide treatment selection and predict patient out- 374
313 improvement in overall survival for the study population comes. In the future, genomic analysis for methotrexate 375
314 [16]. targets in malignant cells in the CSF may be of value in iden- 376
315 The combination of intrathecal chemotherapy with radi- tifying patients most likely to response to HD-MTX [21]. 377
316 ation therapy has also been evaluated. In a Phase II single-
317 arm study by Pan et al., the efficacy and safety of combining
318 intrathecal chemotherapy with involved field radiotherapy
Conclusion 378

319 for treating LM in advanced solid tumors was studied. A

320 total of 59 patients with various solid tumors were enrolled. HD-MTX is a viable treatment option for patients with LM in 379

321 Only 11 patients (19%) had breast cancer. The overall clini- breast cancer, and in select cases, the use of HD-MTX may 380

322 cal response rate was 86%; however, the median overall sur- be associated with prolonged survival. Incorporating HD- 381

323 vival was only 6.5 months with a 1-year survival rate of 21%. MTX as part of a multimodality treatment plan for breast 382

324 Furthermore, neurotoxicity was observed in 26% of patients, cancer with LM may be the best approach to therapy. Addi- 383

325 with 5% of patients suffering severe neurotoxicity and two tional prospective studies are needed to better clarify the 384

326 patients dying from treatment-related neurotoxicity [19]. role of HD-MTX for breast cancer patients with LM. 385

327 They concluded that a combination of intrathecal

328 chemotherapy and radiation therapy is a possible treatment
329 option for LM in metastatic solid tumors. However, this Declaration of Competing Interest 386

330 treatment approach is associated with significant neurotox-

331 icity and does not appear to demonstrate a significant sur- The authors declared that there is no conflict of interest. 387

332 vival advantage.

333 Data supporting the use of systemic chemotherapy for LM References 388
334 are limited to case reports and small case series as most
335 patients with LM are excluded from larger clinical trials. [1] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo 389
336 Observed efficacy has been seen in a limited number of reg- M, et al. Cancer incidence and mortality worldwide: sources, 390
337 imens that have adequate CNS penetration. HD-MTX has methods and major patterns in GLOBOCAN 2012. Int J Cancer 391
338 been shown in retrospective studies and case reports to 2015;136:E359–86. 392

339 have significant efficacy when compared to other therapies [2] Howlader N, Chen VW, Ries LAG, Loch MM, Lee R, DeSantis C, 393

340 for patients with LM [10–12]. et al. Overview of breast cancer collaborative stage data 394

Please cite this article as: J. T. Kapke, R. J. Schneidewend, Z. A. Jawa et al., High-dose intravenous methotrexate in the management of breast
cancer with leptomeningeal disease: Case series and review of the literature, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.

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 HEMONC 306 No. of Pages 5, Model 6+
17 October 2019
High-dose intravenous methotrexate in the management of breast cancer 5

395 items—their definitions, quality, usage, and clinical implica- [13] Tetef ML, Margolin KA, Doroshow JH, Akman S, Leong LA, 434
396 tions: a review of SEER data for 2004–2010. Cancer Morgan Jr RJ, et al. Pharmacokinetics and toxicity of high-dose 435
397 2014;120:3771–80. intravenous methotrexate in the treatment of leptomeningeal 436
398 [3] Barnholtz-Sloan JS, Chen VW, Ries LA, Loch MM, Lee R, carcinomatosis. Cancer Chemother Pharmacol 2000;46:19–26. 437
399 DeSantis C, et al. Incidence proportions of brain metastases in [14] Carmona-Bayonas A. Concurrent radiotherapy and capecita- 438
400 patients diagnosed (1973 to 2001) in the Metropolitan Detroit bine, followed by high-dose methotrexate consolidation, 439
401 Cancer Surveillance System. J Clin Oncol 2004;22:2865–72. provided effective palliation in a patient with leptomeningeal 440
402 [4] Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. metastases from breast cancer. Ann Oncol 2007;18:199–200. 441
403 Cancer Treat Rev 1999;25:103–19. [15] Santa-Maria CA, Cimino-Mathews A, Moseley KF, Wolff AC, 442
404 [5] Morikawa A, Jordan L, Rozner R, Patil S, Boire A, Pentsova E, Blakely JO, et al. Complete radiologic response and long-term 443
405 et al. Characteristics and outcomes of patients with breast survival with use of systemic high-dose methotrexate for 444
406 cancer with leptomeningeal metastasis. Clin Breast Cancer breast cancer-associated leptomeningeal disease. Clin Breast 445
407 2017;17:23–8. Cancer 2012;12:445–9. 446
408 [6] Le Rhun E, Taillibert S, Zairi F, Devos P, Pierret MF, Dubois F, [16] Niwinska A, Rudnicka H, Murawska M. Breast cancer lep- 447
409 et al. Clinicopathological features of breast cancers predict tomeningeal metastasis: the results of combined treatment 448
410 the development of leptomeningeal metastases: a case-control and the comparison of methotrexate and liposomal cytarabine 449
411 study. J Neurooncol 2011;105:309–15. as intra-cerebrospinal fluid chemotherapy. Clin Breast Cancer 450
412 [7] Jo JC, Kang MJ, Kim JE, Ahn JH, Jung KH, Gong G, et al. 2015;15:66–72. 451
413 Clinical features and outcome of leptomeningeal metastasis in [17] Owonikoko TK, Arbiser J, Zelnak A, Shu HK, Shim H, Robin AM, 452
414 patients with breast cancer: a single center experience. et al. Current approaches to the treatment of metastatic brain 453
415 Cancer Chemother Pharmacol 2013;72:201–7. tumours. Nat Rev Clin Oncol 2014;11:203–22. 454
416 [8] Rudnicka H, Niwinska A, Murawska M. Breast cancer lep- [18] Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship 455
417 tomeningeal metastasis—the role of multimodality treatment. J between neurocognitive function and quality of life after 456
418 Neurooncol 2007;84:57–62. whole-brain radiotherapy in patients with brain metastasis. Int 457
419 [9] Niwinska A, Rudnicka H, Murawska M. Breast cancer lep- J Radiat Oncol Biol Phys 2008;71:64–70. 458
420 tomeningeal metastasis: propensity of breast cancer subtypes [19] Pan Z, Yang G, He H, Zhao G, Yuan T, Li Y, et al. Concurrent 459
421 for leptomeninges and the analysis of factors influencing radiotherapy and intrathecal methotrexate for treating lep- 460
422 survival. Med Oncol 2013;30:408. tomeningeal metastasis from solid tumors with adverse prog- 461
423 [10] Boogerd W, van den Bent MJ, Koehler PJ, Heimans JJ, van der nostic factors: a prospective and single-arm study. Int J Cancer 462
424 Sande JJ, et al. The relevance of intraventricular chemother- 2016;139:1864–72. 463
425 apy for leptomeningeal metastasis in breast cancer: a ran- [20] Mrugala MM, Kim B, Sharma A, Johnson N, Graham C, Kurland 464
426 domised study. Eur J Cancer 2004;40:2726–33. BF, et al. Phase II study of systemic high-dose methotrexate 465
427 [11] Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in and intrathecal liposomal cytarabine for treatment of lep- 466
428 cerebrospinal fluid after intravenous, ventricular and lumbar tomeningeal carcinomatosis from Breast cancer. Clin Breast 467
429 injections. N Engl J Med 1975;293:161–6. Cancer 2019. 468
430 [12] Glantz MJ, Cole BF, Recht L, Akerley W, Mills P, Saris S, et al. [21] Castro BA, Kuang R, Brastianos PK. Novel approaches in genetic 469
431 High-dose intravenous methotrexate for patients with non- characterization and targeted therapy for brain metastases. 470
432 leukemic leptomeningeal cancer: is intrathecal chemotherapy Discov Med 2016;22:237–50. 471
433 necessary? J Clin Oncol 1998;16:1561–7. 472

473

Please cite this article as: J. T. Kapke, R. J. Schneidewend, Z. A. Jawa et al., High-dose intravenous methotrexate in the management of breast
cancer with leptomeningeal disease: Case series and review of the literature, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.

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