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Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case Report and Review of the Literature

Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case... Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 154674, 5 pages http://dx.doi.org/10.1155/2013/154674 Case Report Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case Report and Review of the Literature 1 2 Cristina Dumitrescu and Dominique Lossignol Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo, 121, 1000 Brussels, Belgium Supportive Care Unit, Jules Bordet Institute, Boulevard de Waterloo, 121, 1000 Brussels, Belgium Correspondence should be addressed to Cristina Dumitrescu; cristina.dumitrescu@bordet.be Received 26 November 2012; Accepted 30 December 2012 Academic Editors: P. F. Lenehan, R. Martinez, and R. Yamamoto Copyright © 2013 C. Dumitrescu and D. Lossignol. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report the case of a 65-year-old woman, diagnosed with a breast cancer human epidermal growth factor receptor (HER2) previously negative, who developed leptomeningeal carcinomatosis and was treated with intrathecal (IT) trastuzumab (TST). After vfi e doses of IT trastuzumab, at escalading doses, once weekly, the p atient’s neurological status stabilised, and that result was maintained for two months. er Th e is evidence in the literature that breast cancer receptor status may change over time, and when it occurs, it may modify the therapeutical approach. We reviewed the pertinent literature and concluded that IT trastuzumab might be a promising treatment for patients with HER2-positive breast cancer leptomeningeal carcinomatosis. 1. Case Report one cycle, the patient developed ataxia, vertigo, low back pain, headache, and mild cognitive changes. On brain MRI, A 65-year-old woman was diagnosed in 1996 to have an parenchymal metastatic lesions were stable with no signs invasive ductal breast carcinoma with positive local lymph of leptomeningeal disease. However spinal MRI showed nodes. Tumor HER2 receptors were negative; estrogen recep- multiple leptomeningeal lesions (see Figure 1). tor (ER) and progesterone receptor (PgR) were positive. She A lumbar punction was performed, and the CSF exami- was treated by a combination of doxorubicin and docetaxel nation showed increased protein level (660 mg/dL), normal followed by radiotherapy and vfi e years of hormonotherapy glycorrhachia, and the presence of malignant cells. with tamoxifen. Intrathecal trastuzumab was given weekly through an From 2004 until August 2011 multiple bone, lymph Ommaya reservoir, at doses of 20 mg, 40 mg, and then three node, liver, and parenchyma brain metastases were treated injections of 100 mg weekly. This treatment was associated with various chemotherapeutic regimens and focal radiation with systemic trastuzumab 6 mg/Kg every 3 weeks. Lapatinib therapy. Brain metastases appeared in August 2008 and were treatment was also started but rapidly discontinued because treated by gamma-knife followed by whole brain radiation of digestive toxicity. therapy (WBRT) one month later with partial response. After the rst fi dose of IT treatment no malignant cells Twenty-eight months later a second course of WBRT was applied for parenchymal progression. were found in the CSF analysis. The protein level decreased until normal values (0.15–0.45 g/L) aeft r the fourth dose (see In August 2011 a biopsy of liver metastases revealed the Figures 2 and 3). presence of HER2 receptor, contrary to the first diagnostic of breast biopsy which did not showed the presence of the HER2 Aeft r the rfi st two doses of intrathecal trastuzumab, the neurological status of the patient stabilised and did not receptor [1, 2]. On this liver biopsy the status of ER and PgR deteriorate further. The MRI showed a reduction of the brain was not determined. eTh patient was treated by trastuzumab (4 mg/kg at metastatic lesions and a stabilisation of the leptomeningeal infiltration. loading dose, then 2 mg/kg weekly) and vinorelbine. After 2 Case Reports in Oncological Medicine (a) (b) Figure 1: MRI evidence of leptomeningeal carcinomatosis before treatment with IT trastuzumab. 700 0.12 600 0.1 0.08 0.06 0.04 0.02 Dose 20 mg 40 mg 100 mg 100 mg 100 mg 100 0 Intrathecal trastuzumab Timeline Figure 3: Decreased values of the proteins in the CSF by Ommaya Lumbar punction, during the treatment with IT trastuzumab. punction Ommaya punction Series 1 Figure 2: Decreased values until normal ranges of the CSF protein Trastuzumab is a murine antibody that recognizes the level with IT trastuzumab. First value corresponds to the lumbar extracellular domain of the HER2/Neu receptor and has punction. eTh next values corresponds to the Ommaya reservoir been used successfully for the treatment of breast cancer. functions. But this molecule is unable to penetrate through the blood- brain barrier (BBB) due to its 148000 kiloDa (kD) molecular weight. As usually reported, molecules must not exceed The patient died from hepatic failure due to liver metas- 200 Da to cross the BBB. tases eight weeks aeft r the onset of the leptomeningeal disease In 2000 Pestalozzi and Brignoli [12]measuredthe con- symptoms. centration of trastuzumabinthe CSFina62-year-oldwoman treated with weekly intravenous injections. He demonstrated that a very small amount of the drug penetrates through 2. Discussion theBBB:210ng/dLinthe CSFversus61392ng/dLinthe The first cause of leptomeningeal carcinomatosis is breast serum, 210 minutes aer ft the administration of 120 mg of cancer (43%), followed by the lung cancer (31%) and trastuzumab. In 2007 Stemmler et al. [13]showedthatvalues melanoma (6%) [9, 10]. Only 5% of meningeal metastasis are of CSF trastuzumab were two times higher aer ft radiotherapy diagnosed during the cancer evolution; meanwhile 20% are andthree timeshigherinpresenceofleptomeningealcarci- discovered at the autopsy [11]. nomatosis and radiotherapy [14]. Proteins in the CSF (mg/dL) 30.08.2011 08.09.2011 15.09.2011 22.09.2011 29.09.2011 07.10.2011 Proteins in the CFS (g/L) 08.09.2011 15.09.2011 22.09.2011 29.09.2011 07.10.2011 Case Reports in Oncological Medicine 3 fl ft Table 1: Intrathecal treatments using trastuzumab, alone or in association with other agents. WBRT CSF before ITT MRI CSF aer ITT MRI Clinical Reference Symptoms Intrathecal therapy Toxicity response before ITT Proteins Malignant C before ITT Proteins Malignant C after ITT MTX 6× 15 mg + Ommaya Stemmler et al., ♀ 39 Y +Increased + No data TST 5 mg, 10 mg, Low − No data Improved None 2006 [3] Headache, dizziness 15 mg, 20 mg, 20 mg MTX ♀ 36 Y Peridural PAC Platini et al., Vertigo, amnesia, No data 46× 25 mg TST Stable None − Increased + Normal − No data 2006 [4] mental confusion (17 mo) THI Ommaya ♀ 38 Y Colozza et al., 23× Headache, dizziness, + No lumbar punction LMC+ No data − Stable Improved None 2009 [5] 12.5 mg/3 weeks gait disorder TST Ommaya TST 2× 20 mg, 2× ♀ 31 Y 25 mg, 3× 30 mg, Visual impairment, TST 40 mg q3w× Ferrario et al., right ptosis, 8mo Complete No data None − Normal + No data − Improvement 2009 [6] paralysis of the right TST 40 mg q3w + recovery facial nerve, and left thiotepa 10 mg× foot drop 6mo TST 50mg q3W + 12 mg THI× 13 mo MTX 15 mg + CYT ♀ 43 Y 24 mg + HDC Dizziness, cranial +Increased − LMC+ Increased − Improved None 24 mg + 3× 20 mg nerves palsy. TST, 3× 40 mg TST Mego et al., 2011 [7] No data MTX 15 mg + CYT ♀ 39 Y 24 mg + HDC Headache, dizziness, +Increased + LMC+ 24 mg + TST 1× No data − Improved None cranial nerve palsies, 20 mg, 1× 40 mg, 1 vision disorders × 80 mg, 3× 100 mg ♀ 40 Y LMC+ TST 25 mg + PRD Oliveira et al., Complete Headache, vomiting, (CT scan 25 mg× 25 doses (2 None + No lumbar punction No data Partial response 2011 [8] recovery gait disturbance exam) years) TST: trastuzumab, MTX: methotrexate, THI: thiotepa, HDC: hydrocortisone, PRD: prednisolone, CYT: cytarabine, MRI: magnetic resonance imaging, CSF: cerebrospinal uid, mo: months, CT: computed tomography, WBRT: whole brain radiotherapy, ITT: intrathecal treatment, “+”: presence, “−”: absence, malignant C: malignant cells. 4 Case Reports in Oncological Medicine eTh rfi st treatment using trastuzumab as IT chemother- changing from negative to positive was associated with a apy in HER2-positive breast cancer leptomeningeal carcino- certaindecreaseinERand PgRexpressionbetween primary matosis was reported by Laufman and Forsthoefel in 2001 tumor and liver biopsy. Regitnig et al. [22] explained this by a [15]ina48-year-oldwoman,withnoimmediate positive possible crosstalk between the pathways driven by HER2 and therapeutic eeff ct neither any neurological nor site toxicity. the hormone receptors. Following this, in 2005 Stemmler et al. [3] highlighted the Discordance in the receptor status between primary eeff ctiveness of the IT trastuzumab after using this treatment tumor and metastatic site could also be related to different for a 39-year-old woman with HER2-positive breast cancer factors: transcriptional and posttranscriptional modification who developed headache and dizziness. Five increasing in the gene expression level, that can occur spontaneously doses, by steps of 5 mg, of IT trastuzumab were administered or as a consequence of clonal selection in response to six months after WBRT. eTh patient condition improved, and chemotherapy, immunotherapy, and hormonal therapy; lim- no significant toxicity was observed. ited accuracy and reproducibility of receptor assay; errors due In 2006 Platini et al. [4]published theencouraging to biopsy procedure; real switch in the biology of the disease results of a 17-month treatment with intrathecal trastuzumab [25]. without any clinical adverse events. Ourcasereportand thereviewofthe literature lead us A paper published by Colozza et al. [5] described the case to conclude that IT administration of trastuzumab might of a 38-year-old woman with HER2-positive breast cancer improve or stabilise the consequences of leptomeningeal treated with 12.5 mg of IT trastuzumab every 3 weeks. After involvement by HER2-positive breast cancer with no toxicity. nineteen months the patient showed no toxicity but had an Intrathecal trastuzumab might thus be a promising improved neurological status. A second paper published by treatment for leptomeningeal involvement in HER2-positive Ferrario et al. [6] showed that combined treatment of IT breast cancer patients, and further perspective studies have trastuzumab and thiotepa is a promising and safe approach; to be done to better determine the efficacy, safety, and this conclusion was based on the observation of 31-year- tolerability of this approach. old woman with HER2-positive breast cancer treated with increased doses of IT trastuzumab and then IT trastuzumab Conflict of Interests with thiotepa (see Table 1). The hypothesis of using a combined IT treatment was eTh authors have no conflict of interests to declare. successfully applied by Mego et al. [7]inthe case of two HER2-positive breast cancer patients; the treatment con- Acknowledgments sisted in the association of trastuzumab with hydrocortisone and cytarabine. The neurological status improved in both eTh authors thank Professors Jerzy Hildebrand and Jean patients, and no malignant cells were further detected in the Klastersky for their contribution and review of the paper. CSF. In a paper published by Lombardi et al. [9] in 2011, References it is clearly indicated that IT trastuzumab therapy lacks od significant toxicity and can result in significant efficacy [1] A. C. Wol,M ff .E.Hammond,J.N.Schwartzetal.,“ASCO/CAP compared to other intrathecal drugs (topotecan, etoposide, guideline recommendations for human epidermal growth fac- gemcitabine,Α interferon, and alpha interleukin). tor receptor 2 testing in breast cancer,” Archives of Pathology & Finally in a paper published by Oliveira et al. [8]in2001, Laboratory Medicine,vol.131,2007. sixty-seven administrations of 25 mg of IT trastuzumab with [2] C. Colpaert and R. Salgado, “Belgian guidelines for Her2/neu prednisolone resulted in complete recovery of neurological testing in breast cancer,” Belgian Journal of Medical Oncology, vol. 1, pp. 22–29, 2007. symptoms in a 40-year-old woman. [3] H.J.Stemmler, M. Schmitt,N.Harbeck et al., “Application of Sincethentrastuzumab hadbeeniteratively used as intrathecal trastuzumab (Herceptin) for treatment of meningeal intrathecal treatment for the HER2-positive breast can- carcinomatosis in HER2-overexpressing metastatic breast can- cer brain and leptomeningeal metastasis, with no toxicity, cer,” Oncology Reports,vol.15, no.5,pp. 1373–1377, 2006. increased overall survival, and no chemical interactions [16– [4] C.Platini,J.Long, andS.Walter, “Meningeal carcinomatosis 19]. from breast cancer treated with intrathecal trastuzumab,” Lancet There is evidence in the literature [ 20–24]thattumor Oncology,vol.7,no. 9, pp.778–780,2006. receptor status may change over time, and when it occurs, it [5] M. Colozza, E. Minenza, S. Gori et al., “Extended survival of may modify the therapeutical approach. a HER-2-positive metastatic breast cancer patient with brain In a recent paper published in 2011, Curigliano et al. [25] metastases also treated with intrathecal trastuzumab,” Cancer evaluatedthe discordancerateofER, PgR, andHER2status Chemotherapy and Pharmacology,vol.63, no.6,pp. 1157–1159, between primary tumor and liver metastases, with a potential impact on treatment choice. eTh study was conducted on 255 [6] C. Ferrario, A. Davidson, N. Bouganim, R. Aloyz, and L. patients over a ten-year period. Changes in the HER2 status C. Panasci, “Intrathecal trastuzumab and thiotepa for lep- were observed in 172 patients as follows: 17 of 54 patients tomeningeal spread of breast cancer,” Annals of Oncology,vol. (31.5%) changed their status from positive to negative and 20,no. 4, pp.792–795,2009. 7 of 118 patients (5.9%) changed their HER2 status from [7] M. Mego, Z. Sycova-Mila, J. Obertova et al., “Intrathecal admin- negative to positive. eTh study also revealed that HER2 status istration of trastuzumab with cyrarabine and methotrexate in Case Reports in Oncological Medicine 5 breast cancer patients with leptomeningeal carcinomatosis,” The [24] E. Amir, M. Clemons, O. C. Freedman et al., “Tissue confirma- Breast, vol. 20, no. 5, pp. 478–480, 2011. tion of disease recurrence in patients with breast cancer: pooled analysis of two large prospective studies,” Journal of Clinical [8] M. Oliveira, S. Braga, J. L. Passos-Coelho, R. Fonseca, and J. Oncology,vol.28, p. 15s, 2010,abstractno. 1007. Oliveira, “Complete response in HER2+ leptomeningeal car- cinomatosis from breast cancer with intrathecal trastuzumab,” [25] G. Curigliano, V. Bagnardi, G. Viale et al., “Should liver Breast Cancer Research and Treatment,vol.127,no. 3, pp.841– metastases of breast cancer be biopsied to improve treatment 844, 2011. choice?” Annals of Oncology, vol. 22, no. 10, pp. 2227–2233, 2011. [9] G. Lombardi, F. Zustovich, P. Farina et al., “Neoplastic menin- gitis from solid tumors: new diagnostic and therapeutic approaches,” The Oncologist ,vol.16, pp.1175–1188, 2011. [10] E. Le Rhun, S. Tailibert, F. Zairi et al., “Clinicopathological features of breast cancers predict the development of lep- tomeningeal metastases: a case-control study,” Journal of Neuro- Oncology,vol.105,no. 2, pp.309–315,2011. [11] C. Platini, “Trastuzumab and blood-brain barrier,” Bulletin du Cancer, vol. 94, no. 10, pp. 857–859, 2007. [12] B. C. Pestalozzi and S. Brignoli, “Trastuzumab in CSF,” Journal of Clinical Oncology,vol.18, no.11, pp.2349–2351,2000. [13] H.J.Stemmler, M. Schmitt,A.Willems, H. Bernhard,N. Harbeck, and V. Heinemann, “Ratio of trastuzumab levels in serumandcerebrospinalufl idisalteredinHER2-positivebreast cancer patients with brain metastases and impairment of blood- brain barrier,” Anti-Cancer Drugs, vol. 18, no. 1, pp. 23–28, 2007. [14] M. Gutierrez, S. Lyazidi, L. Brasseur, F. Cvitkovic, and R. Le Scodan, “Menin ´ gites carcinomateuses des cancers du sein surexprimant HER2: pour un traitement specifiq ´ ue?” Bulletin du Cancer, vol. 98, no. 4, pp. 417–424, 2011. [15] L.R.Laufman andK.F.Forsthoefel,“Useofintrathecal trastuzumab in a patient with carcinomatous meningitis,” Clin- ical Breast Cancer,vol.2,no. 3, p. 235, 2001. [16] W. Boogerd, M. J. van den Bent, P. J. Koehler et al., “eTh relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study,” European Journal of Cancer, vol. 40, no. 18, pp. 2726–2733, 2004. [17] H. Gauthier, M. N. Guilhaume, F. C. Bidard et al., “Survival of breast cancer patients with meningeal carcinomatosis,” Annals of Oncology,vol.21, no.11, pp.2183–2187,2010. [18] H. Rudnicka, A. Niwinska, ´ and M. Murawska, “Breast cancer leptomeningeal metastasis—the role of multimodality treat- ment,” Journal of Neuro-Oncology,vol.84, no.1,pp. 57–62, 2007. [19] R. H. Baculi, S. Suki, J. Nisbett, N. Leeds, and M. Groves, “Meningeal carcinomatosis from breast carcinoma responsive to trastuzumab,” JournalofClinicalOncology,vol.19, no.13, pp. 3297–3298, 2001. [20] C. Simmons, N. Miller, W. Geddie et al., “Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases?” Annals of Oncology,vol.20, no.9,pp. 1499–1504, 2009. [21] S. J. Aitken,J.S.Thomas,S.P.Langdon,D.J.Harrison, and D. Faratian, “Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases,” Annals of Oncology,vol.21, no.6,pp. 1254–1261, [22] P. Regitnig,W.Schippinger,M.Lindbauer,H.Samonigg, and S. F. Lax, “Change of HER-2/neu status in a subset of distant metastases from breast carcinomas,” Journal of Pathology,vol. 203, no. 4, pp. 918–926, 2004. [23] A. Lipton, K. Leitzel, S. M. Ali et al., “Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy,” Cancer, vol. 104, no. 2, pp. 257–263, 2005. 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Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case Report and Review of the Literature

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Copyright © 2013 Cristina Dumitrescu and Dominique Lossignol. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 154674, 5 pages http://dx.doi.org/10.1155/2013/154674 Case Report Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case Report and Review of the Literature 1 2 Cristina Dumitrescu and Dominique Lossignol Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo, 121, 1000 Brussels, Belgium Supportive Care Unit, Jules Bordet Institute, Boulevard de Waterloo, 121, 1000 Brussels, Belgium Correspondence should be addressed to Cristina Dumitrescu; cristina.dumitrescu@bordet.be Received 26 November 2012; Accepted 30 December 2012 Academic Editors: P. F. Lenehan, R. Martinez, and R. Yamamoto Copyright © 2013 C. Dumitrescu and D. Lossignol. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report the case of a 65-year-old woman, diagnosed with a breast cancer human epidermal growth factor receptor (HER2) previously negative, who developed leptomeningeal carcinomatosis and was treated with intrathecal (IT) trastuzumab (TST). After vfi e doses of IT trastuzumab, at escalading doses, once weekly, the p atient’s neurological status stabilised, and that result was maintained for two months. er Th e is evidence in the literature that breast cancer receptor status may change over time, and when it occurs, it may modify the therapeutical approach. We reviewed the pertinent literature and concluded that IT trastuzumab might be a promising treatment for patients with HER2-positive breast cancer leptomeningeal carcinomatosis. 1. Case Report one cycle, the patient developed ataxia, vertigo, low back pain, headache, and mild cognitive changes. On brain MRI, A 65-year-old woman was diagnosed in 1996 to have an parenchymal metastatic lesions were stable with no signs invasive ductal breast carcinoma with positive local lymph of leptomeningeal disease. However spinal MRI showed nodes. Tumor HER2 receptors were negative; estrogen recep- multiple leptomeningeal lesions (see Figure 1). tor (ER) and progesterone receptor (PgR) were positive. She A lumbar punction was performed, and the CSF exami- was treated by a combination of doxorubicin and docetaxel nation showed increased protein level (660 mg/dL), normal followed by radiotherapy and vfi e years of hormonotherapy glycorrhachia, and the presence of malignant cells. with tamoxifen. Intrathecal trastuzumab was given weekly through an From 2004 until August 2011 multiple bone, lymph Ommaya reservoir, at doses of 20 mg, 40 mg, and then three node, liver, and parenchyma brain metastases were treated injections of 100 mg weekly. This treatment was associated with various chemotherapeutic regimens and focal radiation with systemic trastuzumab 6 mg/Kg every 3 weeks. Lapatinib therapy. Brain metastases appeared in August 2008 and were treatment was also started but rapidly discontinued because treated by gamma-knife followed by whole brain radiation of digestive toxicity. therapy (WBRT) one month later with partial response. After the rst fi dose of IT treatment no malignant cells Twenty-eight months later a second course of WBRT was applied for parenchymal progression. were found in the CSF analysis. The protein level decreased until normal values (0.15–0.45 g/L) aeft r the fourth dose (see In August 2011 a biopsy of liver metastases revealed the Figures 2 and 3). presence of HER2 receptor, contrary to the first diagnostic of breast biopsy which did not showed the presence of the HER2 Aeft r the rfi st two doses of intrathecal trastuzumab, the neurological status of the patient stabilised and did not receptor [1, 2]. On this liver biopsy the status of ER and PgR deteriorate further. The MRI showed a reduction of the brain was not determined. eTh patient was treated by trastuzumab (4 mg/kg at metastatic lesions and a stabilisation of the leptomeningeal infiltration. loading dose, then 2 mg/kg weekly) and vinorelbine. After 2 Case Reports in Oncological Medicine (a) (b) Figure 1: MRI evidence of leptomeningeal carcinomatosis before treatment with IT trastuzumab. 700 0.12 600 0.1 0.08 0.06 0.04 0.02 Dose 20 mg 40 mg 100 mg 100 mg 100 mg 100 0 Intrathecal trastuzumab Timeline Figure 3: Decreased values of the proteins in the CSF by Ommaya Lumbar punction, during the treatment with IT trastuzumab. punction Ommaya punction Series 1 Figure 2: Decreased values until normal ranges of the CSF protein Trastuzumab is a murine antibody that recognizes the level with IT trastuzumab. First value corresponds to the lumbar extracellular domain of the HER2/Neu receptor and has punction. eTh next values corresponds to the Ommaya reservoir been used successfully for the treatment of breast cancer. functions. But this molecule is unable to penetrate through the blood- brain barrier (BBB) due to its 148000 kiloDa (kD) molecular weight. As usually reported, molecules must not exceed The patient died from hepatic failure due to liver metas- 200 Da to cross the BBB. tases eight weeks aeft r the onset of the leptomeningeal disease In 2000 Pestalozzi and Brignoli [12]measuredthe con- symptoms. centration of trastuzumabinthe CSFina62-year-oldwoman treated with weekly intravenous injections. He demonstrated that a very small amount of the drug penetrates through 2. Discussion theBBB:210ng/dLinthe CSFversus61392ng/dLinthe The first cause of leptomeningeal carcinomatosis is breast serum, 210 minutes aer ft the administration of 120 mg of cancer (43%), followed by the lung cancer (31%) and trastuzumab. In 2007 Stemmler et al. [13]showedthatvalues melanoma (6%) [9, 10]. Only 5% of meningeal metastasis are of CSF trastuzumab were two times higher aer ft radiotherapy diagnosed during the cancer evolution; meanwhile 20% are andthree timeshigherinpresenceofleptomeningealcarci- discovered at the autopsy [11]. nomatosis and radiotherapy [14]. Proteins in the CSF (mg/dL) 30.08.2011 08.09.2011 15.09.2011 22.09.2011 29.09.2011 07.10.2011 Proteins in the CFS (g/L) 08.09.2011 15.09.2011 22.09.2011 29.09.2011 07.10.2011 Case Reports in Oncological Medicine 3 fl ft Table 1: Intrathecal treatments using trastuzumab, alone or in association with other agents. WBRT CSF before ITT MRI CSF aer ITT MRI Clinical Reference Symptoms Intrathecal therapy Toxicity response before ITT Proteins Malignant C before ITT Proteins Malignant C after ITT MTX 6× 15 mg + Ommaya Stemmler et al., ♀ 39 Y +Increased + No data TST 5 mg, 10 mg, Low − No data Improved None 2006 [3] Headache, dizziness 15 mg, 20 mg, 20 mg MTX ♀ 36 Y Peridural PAC Platini et al., Vertigo, amnesia, No data 46× 25 mg TST Stable None − Increased + Normal − No data 2006 [4] mental confusion (17 mo) THI Ommaya ♀ 38 Y Colozza et al., 23× Headache, dizziness, + No lumbar punction LMC+ No data − Stable Improved None 2009 [5] 12.5 mg/3 weeks gait disorder TST Ommaya TST 2× 20 mg, 2× ♀ 31 Y 25 mg, 3× 30 mg, Visual impairment, TST 40 mg q3w× Ferrario et al., right ptosis, 8mo Complete No data None − Normal + No data − Improvement 2009 [6] paralysis of the right TST 40 mg q3w + recovery facial nerve, and left thiotepa 10 mg× foot drop 6mo TST 50mg q3W + 12 mg THI× 13 mo MTX 15 mg + CYT ♀ 43 Y 24 mg + HDC Dizziness, cranial +Increased − LMC+ Increased − Improved None 24 mg + 3× 20 mg nerves palsy. TST, 3× 40 mg TST Mego et al., 2011 [7] No data MTX 15 mg + CYT ♀ 39 Y 24 mg + HDC Headache, dizziness, +Increased + LMC+ 24 mg + TST 1× No data − Improved None cranial nerve palsies, 20 mg, 1× 40 mg, 1 vision disorders × 80 mg, 3× 100 mg ♀ 40 Y LMC+ TST 25 mg + PRD Oliveira et al., Complete Headache, vomiting, (CT scan 25 mg× 25 doses (2 None + No lumbar punction No data Partial response 2011 [8] recovery gait disturbance exam) years) TST: trastuzumab, MTX: methotrexate, THI: thiotepa, HDC: hydrocortisone, PRD: prednisolone, CYT: cytarabine, MRI: magnetic resonance imaging, CSF: cerebrospinal uid, mo: months, CT: computed tomography, WBRT: whole brain radiotherapy, ITT: intrathecal treatment, “+”: presence, “−”: absence, malignant C: malignant cells. 4 Case Reports in Oncological Medicine eTh rfi st treatment using trastuzumab as IT chemother- changing from negative to positive was associated with a apy in HER2-positive breast cancer leptomeningeal carcino- certaindecreaseinERand PgRexpressionbetween primary matosis was reported by Laufman and Forsthoefel in 2001 tumor and liver biopsy. Regitnig et al. [22] explained this by a [15]ina48-year-oldwoman,withnoimmediate positive possible crosstalk between the pathways driven by HER2 and therapeutic eeff ct neither any neurological nor site toxicity. the hormone receptors. Following this, in 2005 Stemmler et al. [3] highlighted the Discordance in the receptor status between primary eeff ctiveness of the IT trastuzumab after using this treatment tumor and metastatic site could also be related to different for a 39-year-old woman with HER2-positive breast cancer factors: transcriptional and posttranscriptional modification who developed headache and dizziness. Five increasing in the gene expression level, that can occur spontaneously doses, by steps of 5 mg, of IT trastuzumab were administered or as a consequence of clonal selection in response to six months after WBRT. eTh patient condition improved, and chemotherapy, immunotherapy, and hormonal therapy; lim- no significant toxicity was observed. ited accuracy and reproducibility of receptor assay; errors due In 2006 Platini et al. [4]published theencouraging to biopsy procedure; real switch in the biology of the disease results of a 17-month treatment with intrathecal trastuzumab [25]. without any clinical adverse events. Ourcasereportand thereviewofthe literature lead us A paper published by Colozza et al. [5] described the case to conclude that IT administration of trastuzumab might of a 38-year-old woman with HER2-positive breast cancer improve or stabilise the consequences of leptomeningeal treated with 12.5 mg of IT trastuzumab every 3 weeks. After involvement by HER2-positive breast cancer with no toxicity. nineteen months the patient showed no toxicity but had an Intrathecal trastuzumab might thus be a promising improved neurological status. A second paper published by treatment for leptomeningeal involvement in HER2-positive Ferrario et al. [6] showed that combined treatment of IT breast cancer patients, and further perspective studies have trastuzumab and thiotepa is a promising and safe approach; to be done to better determine the efficacy, safety, and this conclusion was based on the observation of 31-year- tolerability of this approach. old woman with HER2-positive breast cancer treated with increased doses of IT trastuzumab and then IT trastuzumab Conflict of Interests with thiotepa (see Table 1). The hypothesis of using a combined IT treatment was eTh authors have no conflict of interests to declare. successfully applied by Mego et al. [7]inthe case of two HER2-positive breast cancer patients; the treatment con- Acknowledgments sisted in the association of trastuzumab with hydrocortisone and cytarabine. The neurological status improved in both eTh authors thank Professors Jerzy Hildebrand and Jean patients, and no malignant cells were further detected in the Klastersky for their contribution and review of the paper. CSF. In a paper published by Lombardi et al. [9] in 2011, References it is clearly indicated that IT trastuzumab therapy lacks od significant toxicity and can result in significant efficacy [1] A. C. Wol,M ff .E.Hammond,J.N.Schwartzetal.,“ASCO/CAP compared to other intrathecal drugs (topotecan, etoposide, guideline recommendations for human epidermal growth fac- gemcitabine,Α interferon, and alpha interleukin). tor receptor 2 testing in breast cancer,” Archives of Pathology & Finally in a paper published by Oliveira et al. 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