leptomeningeal carcinomatosis is a rare but fatal manifestation of metastatic breast cancer , with limited treatment options .
median overall survival of untreated patients with leptomeningeal carcinomatosis is only 4 - 6 weeks .
although the prognosis for patients with breast cancer and leptomeningeal carcinomatosis is relatively good compared with that of patients with other solid tumors , overall survival is 3 - 5 months .
investigation of intrathecal ( it ) treatment with trastuzumab for leptomeningeal carcinomatosis is currently underway ; however , there has been no consensus .
we report on two cases of human epidermal growth factor receptor 2 positive ( her2 + ) breast cancer treated with it trastuzumab for leptomeningeal carcinomatosis .
a 47-year - old woman presented with a palpable mass on the left breast in may 2003 .
a modified radical mastectomy was performed , and her2 + infiltrating ductal carcinoma ( stage iiib , nuclear grade i , estrogen receptor [ er]+ , progesterone receptor [ pr]+ , her2 + [ immunohistochemistry 2 + and fluorescence in situ hybridization+ ] ) was confirmed by histopathological examination .
metastasis to nine of 10 lymph nodes was detected , thus six cycles of adjuvant chemotherapy with cyclophosphamide , doxorubicin , and 5-fluorouracil ( 5-fu ) were given , followed by adjuvant radiation therapy and hormonal therapy with toremifene . in february 2005 , she developed symptoms of central nervous system ( cns ) involvement , including headache , nausea , and vomiting
. contrast - enhanced magnetic resonance imaging ( mri ) of the brain showed multiple metastatic tumor masses in the cerebrum and cerebellum .
she received whole brain radiotherapy for the brain metastases and started palliative hormone therapy with goserelin plus anastrozole . despite improvement in some brain metastatic lesions with therapy , in april 2007
the treatment was changed to goserelin plus tamoxifen and was continued until february 2010 when metastases to the right supraclavicular lymph node , right neck , and chest wall were noted at restaging .
after she underwent navigation - guided tumor mass removal of brain metastases and excision of the right chest wall mass in april 2010 , she received three cycles of chemotherapy with docetaxel plus doxorubidin .
she was subsequently treated with four additional palliative lines of chemotherapy , including 14 cycles of intravenous ( iv ) trastuzumab ( july 2010-april 2011 ) , xeloda plus lapatinib ( may 2011-december 2011 ) , gemcitabine plus cisplatin ( february 2012 , 1 cycle ) , and cmf ( cyclophosphamide , methotrexate plus 5-fu , march 2012-may 2012 , 3 cycles ) .
she underwent stereotatic radiosurgery ( srs ) twice for brain metastases in 2008 and 2011 . in april 2012 ,
the patient developed headache , vomiting , and gait disturbance . newly visible and increased multifocal enhancing nodules in both frontal , the right parietal , and
metastases to the liver , common bile duct , lung , and right pleura were also confirmed by positron emission tomography - computed tomography .
after srs for parenchymal metastases of the brain , weekly it 50 mg trastuzumab plus it 15-mg methotrexate through the ommaya reservoir was begun for the leptomeningeal nodules .
although she presented with mild weakness of the lower extremities , brain mri showed remarkable improvement in the leptomeningeal nodules after 5 months of it chemotherapy ( fig .
in addition , csf cytology was free of malignant or atypical cells during it therapy , with com - plete resolution of symptoms in 2 days .
the therapy was well tolerated , and she received 20 administrations of weekly it trastuzumab plus methotrexate over 7 months .
the it methotrexate was stopped transiently due to gait disturbance , but no evidence of newly developed enhancing nodules was observed on brain mri until january 2013 ( fig .
she continued weekly it chemotherapy with a reduced dose of trastuzumab ( 25 mg ) for maintenance therapy and received 59 administrations during 18 months , with complete response of the brain mass , indicating complete disappearance of the radiological findings compared to the baseline examination .
unfortunately , in november 2013 , she refused further treatment due to progression of systemic disease and poor performance status .
she died 2 months after the last it trastuzumab administration in january 2014 , after surviving more than 20 months since the diagnosis of leptomeningeal carcinomatosis . a 42-year - old woman presented with a palpable mass on the right breast in july 2008 .
histopathological examination of the specimens sampled by fine - needle biopsy revealed her2 amplified infiltrating ductal carcinoma ( nuclear grade ii , intermediate , er , pr , her2 3 + ; clinical stage ct2n1m0 , iib ) .
after receiving four cycles of neoadjuvant chemotherapy with doxorubicin and docetaxel , she underwent a right half mastectomy with reconstruction in november 2008 .
metastasis to five of 11 axillary lymph nodes was confirmed , thus , two cycles of doxorubicin and docetaxel were administered , followed by adjuvant radiation therapy . in april 2010 , she presented with headache , dizziness , nausea , dysarthria , and showed a tendency to fall to the right .
contrast - enhanced brain mri showed a metastatic tumor mass on the cerebellar vermis , and local relapse was also detected in the right breast by restaging .
the intratentorial supracerebellar tumor mass was removed , and a duroplasty was performed with a modified radical mastectomy in may 2010 .
however , she presented again in january 2012 with symptoms of increased intracranial pressure , including headache , nausea , and vomiting .
2a ) , and csf obtained by lumbar puncture showed a few atypical cells and a slightly elevated protein level ( 58.9 mg / dl ) .
she started weekly it therapy with escalating doses of trastuzumab ( 25 mg > 50 mg ) with iv trastuzumab ( 2 mg / kg ) plus iv paclitaxel ( 80 mg / m ) .
after eight cycles of chemotherapy , she was treated by whole brain radiotherapy , followed by weekly iv and it trastuzumab ( 50 mg ) as maintenance therapy . in may 2012 , after 16 cycles of therapy , her regimen was changed to three weekly iv trastuzumab plus it trastuzumab ( 50 mg ) treatments .
the csf remained free of malignant or even atypical cells during it therapy , and , compared with the brain mri at the beginning of the it trastuzumab cycle , the brain parenchymal metastatic mass and leptomeningeal nodules had decreased in size ( fig .
the patient received a total of 33 administrations of weekly and three weekly iv plus it trastuzumab treatments over 13 months with complete resolution of neurological symptoms(24 and 9 cycles , respectively ) .
although it trastuzumab therapy was stopped due to dizziness , she remains alive , with survival of more than 29 months since being diagnosed with leptomeningeal carcinomatosis .
a 47-year - old woman presented with a palpable mass on the left breast in may 2003 .
a modified radical mastectomy was performed , and her2 + infiltrating ductal carcinoma ( stage iiib , nuclear grade i , estrogen receptor [ er]+ , progesterone receptor [ pr]+ , her2 + [ immunohistochemistry 2 + and fluorescence in situ hybridization+ ] ) was confirmed by histopathological examination .
metastasis to nine of 10 lymph nodes was detected , thus six cycles of adjuvant chemotherapy with cyclophosphamide , doxorubicin , and 5-fluorouracil ( 5-fu ) were given , followed by adjuvant radiation therapy and hormonal therapy with toremifene . in february 2005 , she developed symptoms of central nervous system ( cns ) involvement , including headache , nausea , and vomiting
. contrast - enhanced magnetic resonance imaging ( mri ) of the brain showed multiple metastatic tumor masses in the cerebrum and cerebellum .
she received whole brain radiotherapy for the brain metastases and started palliative hormone therapy with goserelin plus anastrozole . despite improvement in some brain metastatic lesions with therapy , in april 2007
the treatment was changed to goserelin plus tamoxifen and was continued until february 2010 when metastases to the right supraclavicular lymph node , right neck , and chest wall were noted at restaging .
after she underwent navigation - guided tumor mass removal of brain metastases and excision of the right chest wall mass in april 2010 , she received three cycles of chemotherapy with docetaxel plus doxorubidin .
she was subsequently treated with four additional palliative lines of chemotherapy , including 14 cycles of intravenous ( iv ) trastuzumab ( july 2010-april 2011 ) , xeloda plus lapatinib ( may 2011-december 2011 ) , gemcitabine plus cisplatin ( february 2012 , 1 cycle ) , and cmf ( cyclophosphamide , methotrexate plus 5-fu , march 2012-may 2012 , 3 cycles ) .
she underwent stereotatic radiosurgery ( srs ) twice for brain metastases in 2008 and 2011 . in april 2012 ,
the patient developed headache , vomiting , and gait disturbance . newly visible and increased multifocal enhancing nodules in both frontal , the right parietal , and
metastases to the liver , common bile duct , lung , and right pleura were also confirmed by positron emission tomography - computed tomography .
after srs for parenchymal metastases of the brain , weekly it 50 mg trastuzumab plus it 15-mg methotrexate through the ommaya reservoir was begun for the leptomeningeal nodules .
although she presented with mild weakness of the lower extremities , brain mri showed remarkable improvement in the leptomeningeal nodules after 5 months of it chemotherapy ( fig .
in addition , csf cytology was free of malignant or atypical cells during it therapy , with com - plete resolution of symptoms in 2 days .
the therapy was well tolerated , and she received 20 administrations of weekly it trastuzumab plus methotrexate over 7 months .
the it methotrexate was stopped transiently due to gait disturbance , but no evidence of newly developed enhancing nodules was observed on brain mri until january 2013 ( fig .
she continued weekly it chemotherapy with a reduced dose of trastuzumab ( 25 mg ) for maintenance therapy and received 59 administrations during 18 months , with complete response of the brain mass , indicating complete disappearance of the radiological findings compared to the baseline examination .
unfortunately , in november 2013 , she refused further treatment due to progression of systemic disease and poor performance status .
she died 2 months after the last it trastuzumab administration in january 2014 , after surviving more than 20 months since the diagnosis of leptomeningeal carcinomatosis .
a 42-year - old woman presented with a palpable mass on the right breast in july 2008 .
histopathological examination of the specimens sampled by fine - needle biopsy revealed her2 amplified infiltrating ductal carcinoma ( nuclear grade ii , intermediate , er , pr , her2 3 + ; clinical stage ct2n1m0 , iib ) .
after receiving four cycles of neoadjuvant chemotherapy with doxorubicin and docetaxel , she underwent a right half mastectomy with reconstruction in november 2008 .
metastasis to five of 11 axillary lymph nodes was confirmed , thus , two cycles of doxorubicin and docetaxel were administered , followed by adjuvant radiation therapy . in april 2010 , she presented with headache , dizziness , nausea , dysarthria , and showed a tendency to fall to the right .
contrast - enhanced brain mri showed a metastatic tumor mass on the cerebellar vermis , and local relapse was also detected in the right breast by restaging .
the intratentorial supracerebellar tumor mass was removed , and a duroplasty was performed with a modified radical mastectomy in may 2010 .
however , she presented again in january 2012 with symptoms of increased intracranial pressure , including headache , nausea , and vomiting .
2a ) , and csf obtained by lumbar puncture showed a few atypical cells and a slightly elevated protein level ( 58.9 mg / dl ) .
she started weekly it therapy with escalating doses of trastuzumab ( 25 mg > 50 mg ) with iv trastuzumab ( 2 mg / kg ) plus iv paclitaxel ( 80 mg / m ) .
after eight cycles of chemotherapy , she was treated by whole brain radiotherapy , followed by weekly iv and it trastuzumab ( 50 mg ) as maintenance therapy . in may 2012 , after 16 cycles of therapy , her regimen was changed to three weekly iv trastuzumab plus it trastuzumab ( 50 mg ) treatments .
the csf remained free of malignant or even atypical cells during it therapy , and , compared with the brain mri at the beginning of the it trastuzumab cycle , the brain parenchymal metastatic mass and leptomeningeal nodules had decreased in size ( fig .
the patient received a total of 33 administrations of weekly and three weekly iv plus it trastuzumab treatments over 13 months with complete resolution of neurological symptoms(24 and 9 cycles , respectively ) .
although it trastuzumab therapy was stopped due to dizziness , she remains alive , with survival of more than 29 months since being diagnosed with leptomeningeal carcinomatosis .
leptomeningeal carcinomatosis from her2 + breast cancer is rare but important because of its increasing incidence and devastating clinical course .
advances in early diagnosis of cns diseases have been made in recent decades , and systemic chemotherapy , particularly with trastuzumab , has extended survival of patients with her2 + breast cancer , however , despite aggressive treatment , prognosis of leptomeningeal carcinomatosis is still poor .
the blood brain barrier ( bbb ) limits penetration of > 200-kda - sized molecules into the cns .
thus , systemically administered trastuzumab , a 185-kda monoclonal antibody , has only minimal infiltration into the csf through an intact bbb .
pestalozzi and brignoli   reported that the trastuzumab level in csf was 300-fold lower than that in serum of patients with leptomeningeal carcinomatosis receiving iv weekly trastuzumab therapy .
a study by stemmler et al .   also showed that the ratio of median serum trastuzumab level to median csf trastuzumab level was 420:1 , although the ratio improved to 76:1 due to an impaired bbb after radiotherapy .
therefore , it therapy with trastuzumab is an attractive therapeutic option for achievement of a high csf drug concentration with a smaller dose , while reducing systemic drug toxicity . in case studies reporting successful results of it therapy with trastuzumab in patients with leptomeningeal
carcinomatosis from her2 + breast cancer , it trastuzumab was administered in various doses of 25 - 150 mg and using different schedules , including weekly to every 3 weeks .
the case report by hofer et al .   demonstrated the efficacy of it trastuzumab at a dose of 150 mg at 3 weekly intervals , but
there is the question of whether long - term therapy over 6 months with such a high dose is safe and well - tolerable . according to a systematic review and pooled analysis by zagouri et al .
, a significant improvement in overall survival was observed in 68.8% of cases , but no evidence has shown that a particular method is superior to another .
good control of leptomeningeal disease was achieved with it trastuzumab in both of our patients , even though the first patient was heavily treated with five lines of cytotoxic chemotherapy and three lines of hormonal therapy , with survival durations of 20 and 29 months , respectively .
our report also demonstrates that long - term it therapy with relatively high trastuzumab doses ( 25 - 50 mg ) for more than 1 year is safe and efficacious without severe disability of cognitive function .
we suggest that it trastuzumab is a promising treatment for patients with her2 + breast cancer and leptomeningeal carcinomatosis .
further studies are warranted in order to optimize dose , interval , maintenance duration , and combination drugs for treatment , and to standardize consensual response criteria .
 leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer . 
 investigation of intrathecal ( it ) trastuzumab for leptomeningeal carcinomatosis is currently underway ; however , there has been no consensus . 
 we report on two cases of human epidermal growth factor receptor 2 positive ( her2 + ) breast cancer following it trastuzumab for leptomeningeal carcinomatosis . 
 the first patient was treated with weekly it 15 mg methotrexate plus it 50 mg trastuzumab for 7 months , followed by it trastuzumab ( 50 mg > 25 mg ) for 18 months . 
 the other patient received it trastuzumab with systemic chemotherapy ( trastuzumab and/or paclitaxel ) for 13 months . 
 good control of leptomeningeal disease was achieved with it trastuzumab in both patients , with survival durations of 20 and 29 months , respectively . 
 we suggest that it trastuzumab is a promising treatment for patients with her2 + breast cancer and leptomeningeal carcinomatosis . 
Introduction
Case Report
1. Case 1
2. Case 2
Discussion