Prognostic scores for brain metastasis patients.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Brain tumors constitute for 85–90% of all tumors of the central nervous system (CNS) [1]. Brain metastases (BM) are ten times more prevalent than primary tumors of the central nervous system (CNS) and are diagnosed in 10–20% of all cancer patients. The frequency of detection of BM is steadily increasing, which can be explained by such causes. First, this may be due to the increased availability and improvement of diagnostic methods for brain tumors. Second, the use of screening brain examinations of patients with tumors has a high incidence of the CNS metastases. Third, the improved effectiveness of anticancer treatment leads to increased overall survival rates of patients and increased risk of developing BM [2]. All malignant tumors have the potential to provide distant metastasis to the brain. Approximately 75% of all cases of brain metastases are due to patients with lung cancer (40–50%), breast cancer (15–25%), and melanoma (5–20%) [1]. Among the remaining 25%, BM is more predominant in patients with renal cell cancer (4–17%) and gastrointestinal cancer (0.6–3%) [3, 4]. At autopsy, BM are found to be 1.5–3 times more frequent and are detected in more than 65% of patients with lung cancer, 30–40% of patients with malignant melanoma (MM), and 30% of patients with breast cancer (BC). About 85% of metastatic lesions are located in the brain hemispheres, 15% in the cerebellum, and 5% in the brain stem [5].
\nThe aim of this review is to consider important prognostic factors that can determine the treatment decisions and to review the role of blood–brain barrier (BBB) and systemic anticancer treatment (SAT) to manage BM from solid tumors.
\nThe BM patients have significantly worsened the prognosis because the median overall survival (OS) in BM cases varies from 2.79 to 25.3 months. The disease prognosis depends on a number of factors that must be taken into account when determining the treatment algorithm of patients with BM. Table 1 presents prognostic scales assessment of the prognosis in patients with cerebral metastases [6].
\nPrognostic factors | \nRPA | \nRotterdam score | \nSIR | \nBSBM | \nGPA | \nDS-GPA | \n
---|---|---|---|---|---|---|
Age | \n+ | \n— | \n+ | \n— | \n+ | \n+ | \n
Performance status | \nKPS | \nECOG | \nKPS | \nKPS | \nKPS | \nKPS | \n
Extracranial metastases | \n+ | \n+ | \n+ | \n+ | \n+ | \n+ | \n
Control of primary tumor | \n+ | \n— | \n+ | \n+ | \n— | \n— | \n
Number of BM | \n— | \n— | \n+ | \n— | \n+ | \n+ | \n
Volume of BM | \n— | \n— | \n+ | \n— | \n— | \n— | \n
Response to steroids | \n— | \n+ | \n— | \n— | \n— | \n— | \n
Number of classes | \n3 | \n3 | \n3 | \n4 | \n4 | \n4 | \n
Prognostic scores for brain metastasis patients.
RPA: Recursive partitioning analysis; SIR: Score Index for Radiosurgery; BSBM: Basic Score for Brain Metastases; GPA: Graded Prognostic Assessment; DS-GPA: Disease specific Graded Prognostic Assessment; KPS: Karnofsky performance status; ECOG: Eastern Cooperative Oncology Group Score.
Table 1presents the assessment scales of the overall survival prognosis of brain metastases patients have a number of limitations who restrict their use in routine clinical practice and clinical trials. The Recursive partitioning analysis (RPA) scale can be used only if the patient is shown to be carrying out the whole brain radiotherapy (WBRT). RPA cannot be used on patients who underwent palliative surgery, stereotactic radiosurgery (SRS), and/or systemic anticancer therapy, but this treatment option has significant effect on BM patient’s survival. Another limiting factor of the RPA score system is that it does not take into account the size and number of BM. The drawbacks of the Rotterdam score system are the lack of consideration of the patient’s age, number, and size of BM. The most complete predictive system is the Score Index for Radiosurgery (SIR) scale, but it has not been widely used in clinical practice since it does not take into account systemic influence to disease. The Basic Score for Brain Metastases (BSBM) scale is an analogue of RPA scale and takes into account the impact of SRS on the survival of BM patients, but it does not take into account the patient’s age and the effectiveness of systemic drug therapy. In 2007, the Graded Prognostic Assessment (GPA) scoring system was proposed, which took into account four factors: age, Karnofsky performance status (KPS), availability of extracranial metastases, and the number of BM. A number of studies have proved the prognostic significance of these indicators, and the GPA scale is recognized as the most objective and most commonly used scoring system for survival prognosis of BM patients. However, GPA system does not consider the influence of primary tumor type for prognosis of BM, which has different sensitivity to the drug and radiation therapy. To account the influence of the prognostic value of the histological and molecular type of the primary tumor, a Disease Specific Graded Prognostic Assessment (DS-GPA) system was developed. Table 2 presents the factors and prognosis of overall survival rates of patients with BM from lung cancer, MM, BC, renal cell (RCC), and gastrointestinal cancer (GI) [7].
\nPrognostic factor | \nGPA scale score | \nTotal score | \nMedian of overall survival, months (95% СІ) | \n|||||
---|---|---|---|---|---|---|---|---|
0 | \n0.5 | \n1.0 | \n— | \n— | \n\n | |||
Lung cancer | \n||||||||
Age (years) | \n>60 | \n50–60 | \n< 50 | \n— | \n— | \n\n | NSCLC | \nSCLC | \n
KPS | \n<70 | \n70–80 | \n90–100 | \n— | \n— | \n0–1 | \n3.02 (2.63–3.84) | \n2.79 (1.83–3.12) | \n
Extracranial metastases | \nYes | \nn/a | \nNo | \n— | \n— | \n1.5–2.0 | \n5.49 (4.83–6.40) | \n4.90 (4.04–6.51) | \n
— | \n— | \n2.5–3.0 | \n9.43 (8.38–10.80) | \n7.67 (6.27–9.13) | \n||||
Number of BM | \n> 3 | \n2–3 | \n1 | \n— | \n— | \n3.5–4.0 | \n14.78 (11.80–18.80) | \n17.05 (4.70–27.43) | \n
Malignant melanoma | \n\n | |||||||
Prognostic factor | \nGPA scale score | \nTotal score | \nMedian of overall survival, months (95% СІ) | \n|||||
0 | \n1.0 | \n2.0 | \n— | \n— | \n||||
KPS | \n<70 | \n70–80 | \n90–100 | \n— | \n— | \n0–1 | \n3.38 (2.53–4.27) | \n|
Number of BM | \n>3 | \n2–3 | \n1 | \n— | \n— | \n1.5–2.0 | \n4.7 (4.07–5.39) | \n|
2.5–3.0 | \n8.77 (6.74–10.77) | \n|||||||
3.5–4.0 | \n13.23 (9.13–15.64) | \n|||||||
Breast cancer | \n||||||||
Prognostic factor | \nGPA scale score | \nTotal score | \nMedian of overall survival, months (95% СІ) | \n|||||
0 | \n0.5 | \n1.0 | \n1.5 | \n2.0 | \n||||
Age (years) | \n≥ 60 | \n< 60 | \n— | \n— | \n— | \n0–1 | \n3.35 (3.13–3.78) | \n|
KPS | \n≤ 50 | \n60 | \n70–80 | \n90–100 | \n— | \n1.5–2.0 | \n7.70 (5.62–8.74) | \n|
Molecular type | \nTriple negative | \n— | \nLum A | \nHER2-type | \nLum В | \n2.5–3.0 | \n15.07 (12.94–15.87) | \n|
3.5–4.0 | \n25.30 (23.10–26.51) | \n|||||||
Renal cell cancer | \n||||||||
Prognostic factor | \nGPA scale score | \nTotal score | \nMedian of overall survival, months (95% СІ) | \n|||||
0 | \n1.0 | \n2.0 | \n— | \n— | \n||||
KPS | \n<70 | \n70–80 | \n90–100 | \n\n | \n | 0–1 | \n3.27 (2.04–5.10) | \n|
Number of BM | \n>3 | \n2–3 | \n1 | \n\n | \n | 1.5–2.0 | \n7.29 (3.73–10.91) | \n|
2.5–3.0 | \n11.27 (8.80–14.80) | \n|||||||
3.5–4.0 | \n14.77 (9.73–19.79) | \n|||||||
Gastrointestinal cancer | \n||||||||
Prognostic factor | \nGPA scale score | \nTotal score | \nMedian of overall survival, months (95% СІ) | \n|||||
0 | \n1.0 | \n2.0 | \n3.0 | \n4.0 | \n||||
KPS | \n< 70 | \n70 | \n80 | \n90 | \n100 | \n0–1 | \n3.13 (2.37–4.57) | \n|
1.5–2.0 | \n4.40 (3.37–6.53) | \n|||||||
2.5–3.0 | \n6.87 (4.86–11.63) | \n|||||||
3.5–4.0 | \n13.54 (9.76–27.12) | \n
Median of overall patient survival with BM from solid tumors according to the DS-GPA scale prognosis indices.
NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; KPS: Karnofsky performance status; n/a: not applicable; ER: estrogen receptors; PR: progesterone receptors; Her2/neu (ErbB2): human epidermal growth factor receptor 2; Triple negative: ER-negative, PR-negative, Her2/neu-negative; Lum A: ER-positive and/or PR-positive, Her2/neu-negative; HER2-type: ER-negative, PR-negative, Her2/neu-overexpression/amplification; Lum В: ER-positive and/or PR-positive, Her2/neu-overexpression/amplification.
Prognostic scores are very important to take decisions on the most appropriate treatment options for patients with BM in each case. The need for palliative treatment for patients with poor prognosis is controversial, but patients with good prognosis must receive multidisciplinary palliative therapy to increase overall survival rates [8]. Moreover, prognostic score systems can be used to increase the applicability, objectivity, and validity of the clinical trial results that investigate the effectiveness of treatment in patients with BM from various malignant tumors.
\nThe blood-brain barrier (BBB) plays a prominent role in the brain colonization by malignant tumor cells and determines the effectiveness of drug therapy. BBB is a natural obstacle for the penetration of malignant tumor cells within the brain parenchyma. Endothelial cells of brain vessels serve as a mechanical barrier, and astrocytes and microglia are capable of destroying tumor cells. However, after brain colonization, the cerebral endothelial cells, astrocytes, and microglia provide crucial support in the growth and proliferation of tumor cells, and BBB protects cancer cells from influencing the immune system and most anticancer drugs [9].
\nThe penetration of the BBB depends on its functional condition, as well as on the morphological, molecular, and genetic characteristics of tumor cells, that may explain the opportunity of some malignant cells to easily overcome this highly selective barrier relatively. For example, the compound density reduction of the cerebral endothelial cells, which increase the permeability of BBB, was detected in severe CNS diseases such as Alzheimer’s disease, multiple sclerosis, and primary and metastatic brain tumors [10]. The expression CDH2 (N-cadherin), KIFC1, and FALZ genes in a primary tumor in lung cancer patients with BM determine the high cerebral metastatic potential of lung cancer cells. The CDH2 gene encoded N-cadherin (cadherin-2 or neural cadherin (NCAD)) is involved in tumor progression, such as migration and invasion of tumor cells, including in the CNS. Also, in non-small cell lung cancer, patients’ expression of DCUN1D1 squamous cell carcinoma-associated oncogene may promote the tumor cell migration through the BBB and development of BM. High KLF6-SV1 expression in prostate cancer cells associated with poor patient’s survival predict a high risk of lymph nodes, brain, and bones metastasis [11]. Several factors have been identified in breast cancer cells that promote the BC cell migration through the BBB, such as cyclooxygenase-2 (COX2), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and ST6GALNAC5 ((alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide-alpha-2,6-sialyltransferase 5 ST6). The ST6GALNAC5 gene expression is recognized as a tumor cells BBB migration specific marker because COX2 and HB-EGF are associated with the brain and lung metastases. In vitro studies of melanoma cells were shown to increase the BBB permeability by reduce transendothelial electrical resistance of endothelial cells. Expression of melanotransferrin (MELTF, CD228, MAP97, MTF1, MTf, MFI2) and signal transducer and transcriptional activator 3 (STAT3) can serve as potential markers of cerebral metastases in patients with melanoma. The availability of MELTF on the melanoma cell membrane determines their ability to penetrate through the BBB. High levels of STAT3 in melanoma BM compared to primary tumor cells indicate a relationship between STAT3 expression and tumor cell migration to the brain [9]. Thus, the identification of tumor cells specific markers of penetration through the BBB can be a basis for the development of specific methods for the prevention of BM. The main factor of the BM treatment resistance is BBB efflux transporters which prevent the drug’s penetration into the brain parenchyma. Table 3 shows the main drug efflux transporters of the BBB and their substrates and inhibitors [12].
\nEfflux transporter | \nSubstrates | \nInhibitors | \n
---|---|---|
P-glycoprotein | \nDoxorubicin, daunorubicin, docetaxel, paclitaxel, epirubicin, idarubicin, vinblastine, vincristine, etoposide | \nVerapamil, cyclosporine A, quinidine, valspodar, elacridar, biricodar, zosuquidar, tariquidar | \n
MRP1 | \nEtoposide, teniposide, daunorubicin, doxorubicin, epirubicin, melphalan, vincristine, vinblastine | \nProbenecid, sulfinpyrazone, MK-571, cyclosporin A, verapamil, valspodar | \n
MRP2 | \nProbenecid, MK-571, leukotriene C4 | \n|
MRP3 | \nSulfinpyrazone, indomethacin, probenecid | \n|
MRP4 | \nMethotrexate, 6-mercaptopurine, thioguanine | \nProbenecid | \n
MRP5 | \n6-Mercaptopurine, thioguanine | \nProbenecid, sildenafil | \n
MRP6 | \nActinomycin D, cisplatin, daunorubicin, doxorubicin, etoposide | \nProbenecid, indomethacin | \n
BCRP | \nMitoxantrone, methotrexate, SN-38, topotecan, imatinib, erlotinib, gefitinib | \nElacridar, fumitremorgin C | \n
Substrates and inhibitors of the main drug efflux transporters of the BBB.
P-glycoprotein (Pgp, gp170) is a protein encoded by the gene MDR1 (multidrug resistance 1) whose main function is the active removal of many different substances, including some drugs, from the cell cytoplasm to the intercellular environment. Pgp molecules are found in the proximity of the apical membrane of the choroid plexus secretory cells and at the luminal membrane of the brain capillary, which allows transferring most of the Pgp substrates from the endothelium and parenchyma of the BM to the cerebrospinal fluid and blood. The role of Pgp in the maintenance of BBB was investigated through in vivo studies. Studies conducted on MDR1 gene knockout mice revealed an increased effect on brain parenchyma of parenterally administered P-glycoprotein substrates compared with wild-type mice. The use of Pgp-inhibitors in wild-type animals was accompanied by an increase in the brain penetration of Pgp substrates including anticancer drugs (vincristine, paclitaxel, daunorubicin, etc.). Similar results were obtained on using P-glycoprotein inhibitors (verapamil and cyclosporin A) to increase the BBB penetration [7].
\nMultidrug resistance-associated proteins (MRP) are the ABCC family of transporter (ATP-binding cassette subfamily C) proteins, which are an important component determining the selective permeability of the BBB for different drugs [13]. In vivo studies performed on mice with knockout of the MRP1 gene were found to have higher accumulation of MRP1 substrates, including etoposide versus wild-type mice. And after the use of the inhibitor MRP1 (probenecid), a double increase in the concentration of fluorescein in the brain was observed [7].
\nBreast cancer-resistant protein (BCRP, ABCG2). ABCG2 (ATP-binding cassette subfamily G member 2) is an efflux transporter called the breast cancer resistance protein, since it was first detected in the drug-resistant MCF-7 human breast cancer cells [14]. BCRP is an important component in determining BBB permeability, and its concentration in the CNS endothelium is greater than the P-glycoprotein and MRP1 concentrations. In mice with BCRP1 gene knockout, the imatinib concentration in the brain parenchyma was increased 2.5-fold in knockout versus control mice. The administration of a BCRP inhibitor (elacridar) in wild-type mice results in an increase in the penetration of imatinib 4.2 times, while in knockout MDR1 gene mice, elacridar increases cerebral cells absorption of BCRP substrates such as prazosin and mitoxantrone [15].
\nThe structure of BBB in brain metastatic tumors has some features. In contrast to the normal cerebral vascular network, the brain metastases have an increased perivascular space, number, and activity of pinocytotic vacuoles in endothelial cells; these features are more typical for tumor vessels than for the CNS vessels. Thus, metastatic tumor BBB is more permeable than in the normal CNS parenchyma and is more likely to be a capillary barrier than a performed BBB [7].
\nBrain radiotherapy is the standard of palliative care as per the guidelines of clinical practice for patients with BM. In several in vivo studies in rats after brain radiation were such changes observed: dilation and thickening of the blood vessel wall, increase of endothelial cell nuclei, astrocyte hypertrophy, and 60% decrease the P- glycoprotein concentration [7]. These changes in the brain of rats were a prerequisite for a hypothesis about influence of radiation to the BBB permeability and increase in the clinical effectiveness of chemotherapy in patients with BM, because radiation could raise the penetration of anticancer drugs into the brain parenchyma. Murrell D.H., et al. (2016) did not found changes in BBB permeability at the 1st and 11th days after radiation in mice after WBRT therapeutically relevant doses to human equivalent doses. The results of clinical studies have not revealed an increase in clinical effectiveness in the concurrent use of radiation and chemotherapy [16]. The BBB permeability modification under the influence of radiation on the BM at the moment is controversial and needs further study.
\nThe ideal compound to treat BM must have the following physicochemical properties such as low molecular weight, lipophilicity, and absence of ionization at physiological pH. Physicochemical properties of most anticancer drugs not match the above specifications, that limit BBB permeability of drugs, and was a basis for developing ways to deliver drugs to the brain. There are several ways to improve the delivery of substances to the central nervous system, for example, the BBB opening under conditions of temporary osmotic shock, the use of chemical vectors (transporters), increasing the dose and the frequency of drug administration, the use of implants from biodegradable materials, and so on. All methods of increasing drug delivery to the CNS can be attributed to one or more of the three main approaches: change in the chemical structure and/or physicochemical properties, and/or drug dose (concentration), increasing the BBB permeability, and using alternative routes of administration. The low efficiency of most approaches, with the need for performing technically complex manipulations that are accompanied by pronounced side effects and complications, limits their use in everyday clinical practice [17].
\nThe most available methods for improving the drug delivery to BM in routine clinical practice are the use of nanoparticles and efflux transporters inhibitors (Table 3). Application of nanoparticles for targeted drug delivery has several advantages: overcoming chemoresistance, increasing the drug bioavailability and specificity, dose reduction without loss of efficacy, and reduction in adverse reactions. The clinical studies performed on the effectiveness of the nanoparticle application with anticancer drugs served as a basis for the use of these drugs as standard therapy for BM patients. Table 4 shows chemotherapeutic drugs with nanoparticles, the use of which has been approved by the US Food and Drug Administration (FDA) for the treatment BM patients [18].
\nName | \nDescription | \nIndication | \n
---|---|---|
DaunoXome | \nLiposomal daunorubicin | \nFirst-line therapy against advanced Kaposi’s sarcoma associated with HIV | \n
DepoCyt | \nLiposomal cytarabine | \nLymphomatous meningitis | \n
Oncaspar | \nL-asparaginase conjugated with monomethoxypolyethylene glycol (mPEG) | \nAcute lymphoblastic leukemia | \n
Abraxane | \nAlbumin-bound paclitaxel nanospheres | \nPancreatic cancer, NSCLC, breast cancer | \n
Myocet | \nLiposomal doxorubicin | \nBreast cancer | \n
Marqibo | \nLiposomal vincristine | \nAcute lymphoblastic leukemia | \n
Genexol | \nPaclitaxel-loaded polymeric micelle | \nBreast cancer, NSCLC, ovarian cancer | \n
Onivyde | \nLiposomal irinotecan | \nPancreatic cancer | \n
Anticancer nanomedicines approved by the FDA.
The clinical trial results of the efficacy of anticancer nanomedicines and efflux transporter inhibitors in BM patients are encouraging, but further trials are needed to study biodistribution, pharmacokinetics, toxicity, and side effects for inclusion of this drug practice guidelines for the management of CNS tumors.
\nThe decision-making of BM patient’s treatment must rely on some factors such as: the patient Karnofsky performance status; the number, size, and location of BM; the primary tumor type; and the presence and control of extracranial metastases. Table 5 presents palliative treatment options of BM patients depending on the set of predictive factors listed above [7].
\nType of palliative treatment | \nIndications | \n
---|---|
Systemic anticancer therapy | \n- BM from systemic anticancer therapy-sensitive primary tumor; - Asymptomatic BM, detected during planning of systemic anticancer therapy; - BM from PT with identified molecular alteration amenable to targeted therapy; - Poor effect of other treatment options in case presence of potentially effective systemic anticancer agents. | \n
Whole brain radiotherapy | \n- Multiple MGM (> 3–10), especially if the primary tumor is sensitive to radiation therapy; - Large (4 cm) BM; - After surgical resection of a dominant large metastatic tumor and the presence of multiple BM (> 3–10); - BM disease progression during systemic drug therapy; - Salvage therapy for recurrent BM after SRS or WBRT failure. | \n
SRS | \n- Oligo-BM or multi-BM (≤3), especially if primary tumor is known to be radiotherapy resistant; - After surgical resection of a single BM if it diameter > 3 cm and/or BM localized in the posterior cranial fossa; - Local recurrence after surgical resection of a single BM; - Salvage therapy for recurrent oligo-BM or multi-BM (≤ 3) after WBRT failure. | \n
Surgical resection | \n- BM localized (or most of it) in the brain critical structures (eyes, optical tracts, brainstem, etc.); - Oligo-BM (1–2), especially when associated with extensive brain swelling; - If morphological examination of CNS lesions is necessary. | \n
Supportive care alone | \n- Systemic disease progression after several types of palliative therapy in patients with poor performance status. | \n
Decision-making of palliative treatment options of BM patients.
SACT: systemic anticancer therapy, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery.
According to Table 5, patients with brain metastases are not receiving anticancer therapy only if they have progression of the disease after receiving several types of anticancer therapy and them performance status stay poor after adequate supportive care [19].
\nThe evidence of the effectiveness of systemic anticancer therapy in patients with BM is contradictory. Nevertheless, SAСT may be an effective treatment option for patients with BM, because it prolongs overall survival, especially in patients with metastatic lesions in other organs, since the progression of extracranial metastases is a common cause of death of most patients [20]. The BBB is a natural barrier for most anticancer drugs, and it is the primary mechanism responsible for BM resistance to systemic therapy. Several retrospective clinical studies determined that the chemotherapy was effective in 4–38% of patients with BM having various solid tumors [21]. Results are found to be limited on randomized trials on the effectiveness of anticancer drugs, which hinder the development of a generally accepted strategy for effective SACT of BM, especially in patients without extracranial metastases and/or progression after BM local therapy (surgery, radiotherapy). Table 6 presents the effectiveness of chemotherapy in patients with brain metastases from NSCLC, melanoma, and breast cancer.
\nChemotherapy regimen | \nPrimary tumor type | \nNumber of patients | \nResponse rate | \nMedian overall survival (months) | \n
---|---|---|---|---|
Cisplatin + etoposide | \nNSCLC, breast cancer, melanoma | \nTotal 107 (100%): NSCLC–43(40%), BC–56 (52%), MM–8 (8%) | \nTotal 34 (32%): NSCLC–13 (30%), BC–21 (37.5%), MM–0 | \nNSCLC–7.5 (0–91,5+), BC–7.2 (0–67), MM–4.0 (0,5–11.2) | \n
Etirinotecan pegol | \nBC | \n32 | \n5 (15.6%) | \nAll molecular types - 10 (7,8–15.7); Triple negative – 7,6; Lum A and В–12.2; HER2-type–16.1. | \n
Temozolomide | \nNSCLC, breast cancer, melanoma | \nTotal 157 (100%): NSCLC–53(34%), BC–51 (32%), MM–53 (34%) | \nTotal 10 (6%): NSCLC–3 (6%), BC–2 (4%), MM–5 (9%) | \nNSCLC–5.7; BC–n/a, MM–3.3. | \n
Gemcitabine + carboplatin | \nNSCLC | \n66 | \n56 (29%) | \n7.6 (6.3–10.1) | \n
Gemcitabine + paclitaxel | \n64 | \n8.2 (4.6–10.5) | \n||
Carboplatin + paclitaxel | \n64 | \n7.7 (6.1–10.2) | \n||
Cisplatin + gemcitabine | \nBC | \n30 | \n16 (53.3%) | \n10 | \n
18 | \nAll molecular types: 6 (33.4%); Triple negative: 66.6%, Lum A and В: 25%, HER2-type: 12.5% | \nMedian PFS: All molecular types – 5.6 (2.4–8.8); Triple negative – 7.4 (2.4–12.3); Luml A and В: −3.6; HER2-type: 5. | \n||
Carmustine + methotrexate | \nBC | \n48 | \n11 (23%) | \nAll molecular types: 6.9 (4.2–10.7); Her2/neu: overexpression/amplification (n = 8): 14,1; Her2/neu-negative: 5.9 (3,9–8.2). | \n
Pemetrexed | \nNSCLC | \n39 | \n15 (38.4%) | \n10 | \n
Pemetrexed + cisplatin | \nNSCLC | \n43 | \n18 (41.9%) | \n7.4 (5.8–9.6) | \n
Capecitabine + lapatinib | \nBC with Her2/neu: overexpression/amplification | \n799 | \n29.2% (18.5–42.7) | \n11.2 (8.9–14.1) | \n
The efficacy of systemic chemotherapy in patients with brain metastases.
NSCLC: non-small cell lung cancer, BC: breast cancer, MM: malignant melanoma, Triple negative: ER-negative, PR-negative, Her2/neu-negative; Lum A: ER-positive and/or PR-positive, Her2/neu-negative; HER2-type: ER-negative, PR-negative, Her2/neu-overexpression/amplification; Lum В: ER-positive and/or PR-positive, Her2/neu-overexpression/amplification, n/a: not applicable.
In a study performed by Franciosi et al. (1999), 107 patients with BM received a combination of cisplatin 100 mg/m2 (IV day 1) + etoposide 100 mg/m2 (IV on days 1, 3, and 5 or on days 4, 6, and 8) every 21 days, was continued to a maximum of 6 cycles. The distribution according to the primary tumor site was non-small cell lung cancer in 43 (40%) patients, breast cancer in 56 patients (52%), and malignant melanoma in 8 (8%). Among the 107 patients with BM, 7 BC patients achieved complete response (CR) (13%), 3 NSCLC patients achieved CR (7%), and none of the 8 MM patients achieved an objective response. The objective response rate (ORR) of the chemotherapy (CR + partial response (PR)) was recorded in 37.5% of patients with BC and in 30% of patients with NSCLC. The median survival was 7.5 months (range 0–91.5+ months) for patients with NSCLC, 7.2 months (range 0–67 months) for patients with BC, and 4.0 months (range 0.5–11.2 months) for patients with MM. This chemotherapy regime is effective for patients with BM from BC and NSCLC [22].
\nIn open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), was study the effectiveness of etirinotecan pegol 145 mg/m² (IV day 1 every 3 weeks) monotherapy in 32 BC patients with BM previously treated with an anthracyclines, a taxanes, and capecitabine. In this study, there were no recorded cases of CR, partial response was detected only in 5 (15.6%), and 14 (43.8%) patients had disease progression. With a median follow-up of 21.1 months, the progression-free survival (PFS) for 32 patients was 3.1 months (range 1.8–4.0 months), and the median OS 10 months (range 7.8–15.7 months). The efficacy of etirinotecan pegol in BM patients depended on the BC molecular type and median OS was: 16.1 months in HER2-type, 12.2 months in luminal A and B types, and 7.6 months in patients with triple negative BC. The results of the BEACON study recommend the etirinotecan pegol for treatment in BM patients with HER2-type and luminal breast cancer types [23].
\nSiena and co-workers (2010) reported on a nonrandomized multicenter phase II study of 157 patients with cerebral metastases of NSCLC 53 (34%), BC 51 (32%), and melanoma 53 (34%) who received temozolomide 150 mg/m2 per day (oral administration for 1–7 and 15–21 days every 28 or 35 days). The BM complete response was recorded in one (<1%) patient with NSCLC. Among 157 patients, 9 (6%) had PR, and stabilization of disease (SD) was detected in 31 (20%) of 157 patients. The PFS was 66, 58, and 56 days for NSCLC, breast cancer, and melanoma BM patients, respectively. The median OS for patients with NSCLC was 172 days, melanoma was 100 days, and was not applicable in the breast cancer group. The results of this study indicate a low effectiveness of high dose-dense temozolomide regimen for the treatment of brain metastases from NSCLC, BC, and melanoma [24].
\nAt randomized phase 3 clinical trial comparing 3 chemotherapy regimens in 194 patients with clinically stable BM from NSCLC, all patients were randomized into 3 groups: group 1 (n = 66) received the gemcitabine 1000 mg/m2 (on days 1 and 8) + carboplatin AUC 5.5 (on day 1), group 2 (n = 64) received gemcitabine 1000 mg/m2 (on days 1 and 8) + paclitaxel 200 mg/m2 (on day 1), and group 3 (n = 64) received carboplatin AUC 5.5 (on day 1) + paclitaxel 225 mg/m2 (on day 1) IV every 3 weeks, was continued to a maximum of 6 cycles. The study results showed the same clinical efficacy for all three regimens. Median OS was 7.6 months (range 6.3–10.1 months) for patients from group 1, 8.2 months (range 4.6–10.5 months) for group 2, and 7.7 months (range 6.1–10.2 months) for group 3 [25].
\nTwo studies evaluated the efficacy of BM patients from BC treatment with cisplatin + gemcitabine chemotherapy regimen. Naskhletashvili and colleagues reported results of treatment in 30 patients with BC brain metastases who received cisplatin 50 mg/m2 (on days 1 and 8) + gemcitabine 1000 mg/m2 (on days 1 and 8) IV every 3–4 weeks. ORR for chemotherapy was recorded in 6 (53.3%) patients, and the median OS was 10 months [26]. Similar results were obtained by Erten et al. [27]. In this study, 18 BC patients with BM who were treated with cisplatin 30 mg/m2 (on days 1 and 8) + gemcitabine 1000 mg/m2 (on days 1 and 8) IV every 21 days. The ORR depended on the primary tumor molecular type and was 33.4% for all BC molecular types, 66.6% for triple-negative BC, 25% for luminal types, and 12.5% for patients with HER2- type. The overall survival rates of these study patients have not been reported. Median PFS also depended on the type of breast cancer and was greatest in patients with triple-negative breast cancer at 7.4 months (range 2.4–12.3 months); in patients with HER2-type at 5 months, with luminal types at 3.6 and 5.6 months (range 2.6–8.8 months) for all breast cancer molecular types [27].
\nJacot and co-workers reported on 48 breast cancer patients treated with carmustine 100 mg/m2 (on day 1) + methotrexate 600 mg/m2 (on days 1 and 15) IV of a 28-day cycle. Patients with Her2/neu overexpression and/or amplification received trastuzumab 4 mg/kg (on days 1 and 15) IV during each cycle of chemotherapy. The ORR was detected in 11 (23%) patients. The PFS was 4.2 months (range 2.8–5.3 months), and the median OS at 6.9 months (range 4.2–10.7 months) for all BC molecular type. The median OS was different in patients with the Her2/neu overexpression and/or amplification tumors (14.1 months) and without Her2/neu overexpression and/or amplification BC (5.9 months) [28].
\nThe efficacy of pemetrexed in NSCLC patients with BM was evaluated in several studies. Bearz et al. (2009) reported about clinically significant efficacy monotherapy of pemetrexed 500 mg/m2 IV (on day 1) every 3 weeks as a 2- or 3-line chemotherapy. ORR was detected in 15 (38.4%) from 39 patients with BM from NSCLC, and median OS was 10 months. Barlesi et al. (2011) evaluated the efficacy of the regimen pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (IV on day 1) every 3 weeks for 6 cycles. The ORR was recorded in 18 (41.9%) of 43 patients with BM from NSCLC, and the median OS was 7.4 months (range 5.8–9.6 months). The concurrent administration of WBRT with chemotherapy pemetrexed + cisplatin significantly increases the treatment effectiveness according to the results obtained by Dinglin et al. (2013). The ORR of the pemetrexed + cisplatin + WBRT regimen was detected in 28 (68.3%) of 41 NSCLC patients with BM, and median OS was 12.6 months [29].
\nThe efficacy of combination capecitabine and lapatinib for the treatment of Her2/neu overexpression on BC patients with BM has been investigated in several studies. A systematic review and meta-analysis of 12 studies, for total 799 patients with BM from Her2/neu-positive breast cancer, was show revealed ORR was 21.4% (range 11.7-35.9). After excluding from the analysis patients who received lapatinib alone, the ORR was 29.2% (range 18.5–42.7). The median OS of patients with BM from Her2/neu-positive BC was 11.2 months (range 8.9–14.1 months), and PFS was 4.1 months (range 3.1–6.7 months) [30].
\nThe targeted therapies and immunotherapies that have the significant efficacy for treatment on patients with BM from various malignant tumors are presented in Table 7.
\nName | \nPrimary tumor type | \nNumber of patients | \nResponse rate | \nMedian overall survival (months) | \n
---|---|---|---|---|
Gefitinib | \nNSCLC | \n41 | \n36 (87.8%) | \n21.9 (18.5–30.3) | \n
Erlotinib | \n63 | \nn/a | \n26 | \n|
Vemurafenib | \nMM | \ncohort 1–90 cohort 2–56 | \n16 (18%) 10 (18%) | \n8.9 (0.6–34.5) 9.6 (0.7–34.3) | \n
Dabrafenib | \ncohort 1–89 cohort 2–83 | \ncohort 1 V600E–39% V600 K–31% cohort 2 V600E–7% V600 K–22% | \ncohort 1 V600E–7.6; V600K–3.7; cohort 2 V600E–7.2; V600 K–5.0; | \n|
Crizotinib | \nNSCLC | \n20 | \n3 (15%) | \n10.3 | \n
Ceritinib | \nNSCLC | \n124 (ASCEND-1) | \n10* (36%) | \nn/a | \n
140 (ASCEND-2) | \n54 (38.6%) | \nn/a | \n||
50 (ASCEND-3) | \n29 (58%) | \nn/a | \n||
Alectinib | \nNSCLC | \n136 (100%) 50* (37%) 86** (63%) | \n32* (64%) 37** (43%) | \nn/a | \n
Bevacizumab + carboplatin + paclitaxel | \n67 | \n42 (62.7%) | \n16 | \n|
Trastuzumab | \nBC | \n56 | \nn/a | \n10.5 (8.3–17.7) | \n
Lapatinib | \n30 | \nn/a | \n21.4 (12.5–27.1) | \n|
Trastuzumab + lapatinib | \n28 | \nn/a | \n25.9 (18.5–30.1) | \n|
Ipilimumab | \nMM | \ncohort А–51 cohort В–21 | \ncohort А 9 (18%) cohort В 1 (5%) | \ncohort А 7 (4.1–10.8) cohort В 3.7 (1.6–7.3) | \n
Ipilimumab + fotemustine | \nMM | \n20 | \n1 (5%) | \n12.7 (2.7–22.7) | \n
Pembrolizumab | \nNSCLC, MM | \n18 18 | \n6 (33%) 4 (22%) | \n7.7 n/a | \n
The efficacy targeted therapy and immunotherapy in patients with brain metastasis.
Patients with measurable target brain lesions.
Patients without measurable target brain lesions.
n/a, not applicable.
Iuchi et al. [31] reported on 41 patients with BM from epidermal growth factor receptors (EGFR) mutant lung adenocarcinoma treated with gefitinib. Patients were assigned gefitinib 250 mg/day until the disease progression or development of unacceptable toxicity. The ORR was 87.8%, and the median OS and PFR were 21.9 months (range 18.5–30.3 months) 14.5 months (range 10.2–18.3 months), respectively [31].
\nGerber and associates [32] presented the results of treatment on 110 patients with BM EGFR-mutated lung adenocarcinoma. Depending on the treatment regimen, all patients were divided into 3 groups: group 1 (n = 63) patients who received erlotinib day until the disease progression or development of unacceptable toxicity, group 2 (n = 32) was treated only WBRT, group 3 (n = 15) was treated only SRS. The median OS of all 110 patients was 33 months: 26 months in group 1 and 35 and 63 months in groups 2 and 3, respectively [32].
\nAn open-label, single-arm, phase 2, multicenter study was performed to investigate the efficacy of vemurafenib in 146 patients with BM from BRAFV600-mutated melanoma. Patients were divided into two cohorts: cohort 1 (n = 90) patients who had not previously received BM local therapy (radiation therapy or surgery), and previous systemic therapy did not include BRAF or MEK inhibitors; cohort 2 (n = 6) patients with progression of melanoma BM after previous local therapy. ORR was 18% in both cohorts (16 and 10 patients in cohort 1 and 2, respectively). The PFS was 3.7 months (range 0.03–33.4 months) in cohort 1 and 4.0 months (range 0.3–27.4 months) in cohort 2. The median OS was 8.9 months (range 0.6–34.5 months) and 9.6 months (range 0.7–34.3 months) in cohort 1 and 2, respectively [33].
\nAn open-label, phase 2, multicenter study (BREAK-MB) was evaluated to observe the effectiveness of oral administration of dabrafenib 150 mg twice daily in 172 patients with brain parenchyma metastases from melanoma with a mutation of BRAF V600E (139 patients) and V600E (33 patients). Patients were divided into two cohorts: cohort 1 (n = 89) patients who had not previously received BM local therapy (radiotherapy or surgery), cohort 2 (n = 83) patients with intracranial progression of melanoma after previous BM local therapy. The ORR in cohort 1 was 39% and 31% in patients with mutations V600E and V600K, respectively, and in cohort 2 in 7% of patients with mutation V600E and 22% with mutation V600K. The median OS in patients with the V600E mutation was 7.6 and 7.2 months, and 3.7 and 5.0 months in patients with V600K mutation in cohort 1 and 2, respectively. The PFS was 3.7 months in patients with mutations BRAF V600E and V600K in cohort 1 and 2, respectively, and 1.8 months in patients with BRAF V600K mutation in cohort 1, and 3.8 months in patients with BRAF V600K mutation in cohort 2 [34]. Xing P. and associates (2016) presented the results of crizotinib treatment on 20 advanced ALK-rearranged NSCLC patients with baseline brain metastases in Chinese population. The median OS of patients was 10,3 months and PFS was 21,2 months [35].
\nThe efficacy of ceritinib for the treatment of BM in patients with ALK-positive NSCLC was evaluated in the ASCEND-1, ASCEND-2, and ASCEND-3 trials. In the ASCEND-1 study, 124 patients with ALK-positive NSCLC were diagnosed with BM, 98 of the 124 patients had previously received ALK (crizotinib) inhibitor therapy prior to progression, and 26 patients without previously ALK inhibitors treatment. Only 14 patients (10 patients had received crizotinib before and 4 had not received ALK inhibitors before) had investigator-assessed brain lesions selected as target lesions at baseline. In seven of them (four patients after previous therapy with ALK inhibitors and three without previous therapy) was detected PR and in three patients discovered SD (all after previous crizotinib therapy). The PFS was 6.9 months (range 5.4–8.4 months) for all patients or 6.7 months (range 4.9–8.4 months) for patients previously treated with ALK inhibitors and 8.3 months (range 4.6–not applicable) for patients who have not previously received ALK inhibitors [36] .
\nCrino and co-workers [37] reported a single-arm, open-label, multicenter, phase 2 study of ceritinib in a heavily pretreated patient population with ALK-rearranged NSCLC (ASCEND-2) in 140 patients who received at least two lines of therapy including platinum-based chemotherapy and crizotinib. The ORR was 38.6% (range 30.5%–47.2). The median of follow-up time 8.8 months (range, 0.1–19.4 months) and the median PFS was 5.7 months (range 5.4–7.6 months) [37].
\nIn ASCEND-3 trial, efficacy of ceritinib was investigated in 124 ALK-positive NSCLC patients who had not previously received therapy with ALK inhibitors. Among 124 patients included in this study, 50 patients (40%) had BM, and radiation was performed on 27 (54%) patients for brain metastatic lesions. The median PFS was 10.8 months (range 7.3–not available), and ORR was detected in 27 (54%) patients [38].
\nGadgeel and assistants analyzed the results of two studies (NP28761 and NP28673) to investigate the efficacy and safety of the use of alectinib for treating patients with BM from ALK-positive NSCLC with disease progression after previous treatment with crizotinib. Measurable target brain lesions were detected in 50 (37%) patients and in 86 (63%)—without measurable target brain lesions. The disease control rate (DCR) was detected in 32 (64%) patients with measurable target brain lesions (PR = 22%) and in 37 (43%) patients without measurable target brain lesions (PR = 27%). In patients who underwent radiation therapy of BM (n = 95) before started alectinib therapy intracranial response rate (ICRR) was 35.8% versus 58.5% in patients (n = 41) who did not receive previously radiation therapy [39].
\nAt phase II prospective, noncomparative BRAIN study investigated efficacy and safety of combination bevacizumab (15 mg/kg) + carboplatin (AUC 6) + paclitaxel (200 mg/m2) IV every 3 weeks as the first line of treatment of non-squamous NSCLC patients (n = 67) with asymptomatic, previously untreated BM. PR and SD of intracranial metastases was recorded in 42 (62.7%) and 18 (26.9%), respectively. Median PFS was 6.7 months. (5.7–7.1), and the median OS was 16 months [40].
\nIn the retrospective multicenter study, Yap and co-workers [41] evaluated the efficacy of anti-Her2/neu therapy in patients with BM from Her2/neu overexpression BC. Among 280 patients with BM Her2/neu-positive BC, 260 (92.9%) patients underwent radiation therapy, 160 (57.1%) patients underwent chemotherapy, and 114 (40.7%) anti-Her2/neu therapy. Of the 114 patients receiving anti-Her2/neu therapy, 56 (49.1%) patients receive trastuzumab, 30 (26.3%)—lapatinib and 28 (24.6%) trastuzumab plus lapatinib combination. The median OS was significantly higher in patients receiving combined anti-Her2/neu therapy and was 10.5 months (range 8.3–17.7 months) in the trastuzumab group, 21.4 months (range 12.5–27.1 months) in the lapatinib group, and 25.9 months (range 18.5–30.1 months) in patients from the trastuzumab + lapatinib group [41].
\nAn open-label, phase 2 trial investigated efficacy of ipilimumab for the treatment of patients with BM from melanoma. A total of 72 melanoma patients with BM were divided into 2 cohorts: cohort A (n = 51)—patients with asymptomatic BM, cohort B (n = 21)—patients with symptomatic BM and received glucocorticoids. All patients received ipilimumab at 10 mg/kg IV every 3 weeks for a total of 4 cycles. The DCR was 18% in cohort A and 5% in cohort B. Overall survival for 1 year was 31% and 19% with a median OS 7 months (range 4.1–10.8 months) and 3.7 months (range 1.6–7.3 months) in the cohort A and B, respectively [42].
\nIn the NIBIT-M1 study Di Giacomo and co-workers [43] reported on 20 patients with asymptomatic BM from melanoma who received combined systemic therapy of ipilimumab (10 mg/kg IV every 3 weeks for a total of 4 injections) and fotemustine (100 mg/m2 IV weekly total 3 injections). Maintenance therapy was carried out according to the regiment: fotemustine every 3 weeks from 9 weeks of therapy and ipilimumab every 12 weeks from 24 weeks from the onset of systemic therapy to disease progression or patient failure, or to the occurrence of excessive toxicity. Maintenance therapy was carried out according to the regiment: fotemustine every 3 weeks from 9 weeks of therapy and ipilimumab every 12 weeks from 24 weeks from the onset of systemic therapy to disease progression or patient failure, or to the occurrence of excessive toxicity. Seven patients (35%) before systemic treatment were radiotherapy. The ORR was 5% at an immunological response rate was 50%. With median follow-up of 39.9 months, the 3-year OS was 27.8%, and the median OS was 12.7 months.
\nGoldberg et al. [44] in non-randomized, open-label, phase 2 trial was investigated effectiveness of pembolizumab in 36 patients with asymptomatic BM from NSCLC (n = 18) and melanoma (n = 18). The PD-L1 expression in primary tumor was detected in patients with NSCLC only. All patients received pembolizumab 10 mg/kg IV every 2 weeks before disease progression. The ICRR was 33% for NSCLC and 22% for melanoma. The median follow-up was 11.6 months (range 8.5–13.9 months) and median OS was not achieved (NA) in the patients with melanoma BM. The median follow-up was 6.8 months (range 3.1–7.8 months) and median OS was 7.7 months (range 3,5–ND) in the NSCLC patients with BM [44].
\nIn recent decades, significant progress has been made in diagnosing, predicting, and treatment of patients with BM of various malignant tumors. Nevertheless, the successes achieved are not sufficient, since the overall survival rates of patients remain low. Further studies of the mechanisms of metastasis of malignant tumors in the brain can serve as a basis for the development of methods for the prevention of BM, and the study of the role of BBB in the development of resistance to systemic therapy will help develop methods that overcome this natural barrier and increase the effectiveness of antitumor drugs. Applying a multidisciplinary approach to developing patient treatment, tactics using the current flow forecast scales will lead to a more valid appointment of radiation therapy, surgery, systemic antitumor and symptomatic therapy to preserve the neurological and neurocognitive function, and the quality of life of patients.
\nMetals (such as Au and Ag) have been utilized for the majority of plasmonic materials in the visible range. Recently, oxide semiconductors have attracted much attention for use as potential new plasmonic materials. In particular, ZnO: Ga and In2O3: Sn (ITO) are known for use as transparent electrodes due to their metallic conductivity. These oxide semiconductors show surface plasmon resonances (SPRs) in the infrared (IR) range [1, 2]. Propagated SPRs can be excited on metal surfaces using a prism-coupling technique such as a Kretschmann-type attenuated total reflection (ATR) system [3]. Our research group has investigated the optical properties of SPRs excited on ZnO: Ga and ITO film surfaces from the viewpoint of physical characteristics such as field strength and penetration depth [4, 5, 6]. On the other hand, subwavelength materials such as nanorods, nanoparticles (NPs), and nanodots are capable of supporting localized surface plasmon resonances (LSPRs), which can be directly excited by incident light in the absence of a prism-coupling method [7, 8]. Above all, LSPRs confined to NPs can lead to light at the nanoscale when confining the collective oscillations of free electrons into NPs. This LSPR effect further provides strong electric fields (E-fields) on NP surfaces, which contribute to surface-enhanced optical spectroscopy [9]. For example, assembled films consisting of ITO NPs have demonstrated optical enhancements of near-IR luminescence and absorption in the IR range [10, 11]. Therefore, optical studies concerning oxide semiconductor NPs can break new research ground in the area of plasmonics and metamaterials.
\nAn understanding of plasmon damping is very important in order to achieve high-efficiency LSPRs. A number of plasmonic studies of metal NPs have been devoted to investigating the damping processes of LSPRs. For metal NPs, there are two main damping processes, comprising (i) size-dependent surface scattering and (ii) electronic structure-related inter- and intraband damping [12, 13, 14, 15]. The damping processes are closely related to the physical properties of the metals. Therefore, understanding of the damping processes of LSPRs in oxide semiconductor NPs is also important for the control of optical properties. Oxide semiconductor NPs are useful plasmonic materials since their LSPR wavelengths can be widely tuned by electron density in addition to particle size [16, 17, 18]. Carrier control of LSPRs indicates that oxide semiconductors have an additional means of tuning the optical properties in a manner that is not as readily available for metal NPs. In particular, carrier-dependent damping is a specific feature of the plasmonic response in oxide semiconductor NPs. Precise elucidation of the carrier-dependent damping process including structural size is required for the optical design of plasmonic materials based on oxide semiconductor NPs.
\nThe purpose of this chapter is to report on the light interactions of size- and carrier-controlled ITO NPs and to discuss their plasmonic applications in the IR range. We introduce size- and carrier-dependent plasmonic responses and provide information for the physical interpretation of optical spectra. A rigorous approach to the analysis of the optical properties allows us to show a quantitative assessment of the electronic properties in ITO NPs. The employments of Mie theoretical calculations, which can describe well the optical properties of metal NPs, are validated in terms of ITO NPs. Finally, we discuss the optical properties assembled films of ITO NPs for solar-thermal shielding.
\nITO NPs with different Sn contents were fabricated using the chemical thermolysis method with various initial ratios of precursor complexes (C10H22O2)3In and (C10H22O2)4Sn [19]. Indium and tin complexes were thermal heated at 300–350°C for 4 h in a reducing agent, and the mixture was then gradually cooled to room temperature. The resultant mixture produced a pale blue suspension and to which was then added excess ethanol to induce precipitation. Centrifugation and repeated washing were conducted four times using ethanol, which produced dried powders of ITO NPs with a pale blue color. Finally, the powder samples were dispersed in a nonpolar solvent of toluene. Electrophoresis analysis revealed a positive zeta potential of +31 meV for the NPs, which indicated the NPs had non-aggregated states in the solvent due to electrostatic repulsion between NPs. Particle surfaces of the NPs were terminated by organic ligands consisting of fatty acids, which contributed in spatial separation between NPs.
\nOptical absorptions and TEM images of ITO NPs with different electron densities (ne) were examined (Figure 1). TEM images revealed that all NP sizes (D) were ca. 36 nm (Figure 2(a–c)). This indicates that the systematic change in the absorption spectra is related to the Sn content. Absorption measurements were performed using a Fourier-transform infrared (FT-IR) spectrometer. A value of ne was estimated from the absorption spectra by theoretical calculations. The following equation was used to derive absorption intensity (A) from the experimental data [20]:
\nwhere k = 2π(εd)1/2ω/c with c representing the speed of light, εd indicates the host dielectric constants of toluene, εm(ω) is the particle dielectric function, and R is the particle radius. Furthermore, εm(ω) employed the free-electron Drude term with frequency-dependent damping constant, Γ(ω), on the basis that ITO comprised free-electron carriers [20]:
\nAbsorption spectra of ITO NPs with different electron densities. Doping with Sn contents of 0.02, 1, and 5% into the NPs’ induced electron density of 6.3 × 1019 cm−3, 5.7 × 1020 cm−3, and 1.1 × 1021 cm−3, respectively. Dot lines indicate theoretical calculations based on the modified Mie theory [19].
TEM images of ITO NPs with electron densities of (a) 6.3 × 1019 cm−3, (b) 5.7 × 1020 cm−3, and (c) 1.1 × 1021 cm−3 [19].
The plasma frequency (ωp) is given by \n
where f(ω) can be described by f(ω) = [1 + exp{(ω−Γx)/σ}]−1. ΓH and ΓL represent the high-frequency (ω = ∞) and low-frequency (ω = 0) damping, respectively. ΓX and σ represent the change-over frequency and width of the function, respectively.
\nCalculated absorption spectra were very close to the experimental data. ITO NPs doped with Sn content of 0.02, 1, or 5% provided electron density of 6.3 × 1019, 5.7 × 1020, and 1.1 × 2021 cm−3, respectively (Figure 1). We summarized the LSPR resonant peak and absorption intensity as a function of ne (Figure 3(a)). The LSPR resonant peak gradually showed a redshift from the near-IR to mid-IR range with decreasing ne. Additionally, the absorption intensity decreased markedly with decreasing ne. No plasmon excitation was observed in the low ne region below 1019 cm−3. The Mott critical density (Nc) of ITO is estimated as Nc = 6 × 1018 cm−3 (Figure 3(b)). Below the Mott critical density, the impurity band is not overlapped with the Fermi energy (EF) level. ITO results in a band insulator.
\n(a) LSPR resonant peak and absorption intensity of ITO NPs as a function of electron density. (b) a schematic picture of electronic structures of ITO with different ranges of electron density.
However, the EF level combined with the impurity band in the middle ne region from 1019 to 1020 cm−3. At the high ne region above 1020 cm−3, the EF level is placed in a highest occupied state in the conduction band (CB). As a consequence, ITO shows metallic behavior. These results indicated that a large amount of free electrons were required to excite highly efficient plasmon excitations. ITO NPs were suitable for plasmonic materials in the near-IR range.
\nThe two types of damping processes that exist in plasmon excitations of metal NPs are (i) bulk damping and (ii) surface damping. Bulk damping (γB) is related to electron-electron (γe-e), electron-phonon (γe-ph.), and electron-impurity scattering (γe-impurity). These scattering components determine a mean free path (lm) of a free electron. On the other hand, surface scattering is effective when a NP size is smaller than lm, which becomes the main damping process in NPs.
\nSurface scattering (γs) can be described by γs = AvF/lSC for a small nanoparticle, where A is a material constant and vF is the Fermi velocity [vF = ħ/m*(3πne)1/3]. The surface scattering length (lSC) is defined by lSC = 4 V/S, where V is the volume and S is the surface area of the particle [20]. For our ITO NPs, lSC was calculated as 24 nm, which was longer than the lm of ITO (∼10 nm) [22, 23]. For ITO NPs, no surface scattering was effective because the lm of ITO was smaller than lSC. Therefore, it is considered that ITO NPs are mainly related to bulk damping.
\nMetallic conductivity of ITO NPs is obtained by doping with impurity atoms, suggesting that ITO NPs involve electron-impurity scattering in bulk damping. The spectral features of ITO NPs could be fitted using Mie theory with frequency-dependent damping parameter Γ(ω). Figure 4(a) shows absorption spectra of ITO NPs with lowest (5.5 × 1019 cm−3) and highest (1.1 × 1021 cm−3) ne values. For NPs with the lowest ne, a symmetric absorption spectrum was obtained, while an asymmetric spectrum was obtained for NPs with the highest ne. These spectral features were determined by ΓH and ΓL. Figure 4(b) shows the dependence of ΓH and ΓL on electron density. A difference in ΓH and ΓL values was found in the high ne region above 1020 cm−3. Electron-impurity scattering is reflected by ΓL, providing asymmetric LSPR features by broadening in the low photon energy regions. In contrast, the ΓL values (∼70 meV) were the same as those of ΓH in the low ne region below 1020 cm−3, indicating that LSPRs were independent of electron-impurity scattering.
\n(a) Absorption spectra of ITO NPs with ne values of 5.5 × 1019 and 1.1 × 1021 cm−3. (b) Dependence of ΓH (●) and ΓL (○) on electron density. (c) Mobility (μe) as a function of electron density. The μe (black dots) are compared with those obtained using ionized impurity scattering (IIS) process (black line).
The carrier-dependent plasmon response is divided into two ne regions. Region-I comprises low ne below 1020 cm−3, in which coherence of electron oscillation in ITO NPs is not always disturbed by electron-impurity scattering. The spectral features of LSPRs comprise narrow line-widths and symmetric line-shapes. However, absorption intensity is small (Figure 3(a)) since a short mean free path length (lm = 3–4 nm) determines the coherence of electron oscillations in the NPs. This situation is due to insufficient conduction paths. Region-II comprises high ne above 1020 cm−3, in which LSPR excitations become more effective with increasing lm, as a result of increased ne. The lm value of NPs with the highest ne was estimated as 10.7 nm. However, LSPR excitations are influenced by electron-impurity scattering, which generated the asymmetric line-shapes.
\nDegenerated metals on doped oxide semiconductors are generally realized by extrinsic and/or intrinsic dopants. However, the carrier screening effect from background cations is weak in contrast to metals with a short screening length (comprising several angstroms) [24]. Electron-impurity scattering dominates the optical properties of LSPRs in the high ne region. In this work, the maximum lm in ITO NPs was 10.7 nm. Previous reports have detailed long lm values from 14 to 16 nm on ITO films [22, 23]. Control of crystallinity and impurities in ITO NPs will be required to obtain high-efficiency LSPR excitations in the IR range.
\nFigure 5(a) shows the size distribution of ITO NPs, revealing that size distribution gradually increased with increasing particle size (D): D = 10 ± 2.2 nm, 20 ± 3.5 nm, and 36 ± 4.3 nm. Figure 6 shows TEM results of the dependency of NPs on particle size. In particular, NPs with D = 36 nm showed well-developed facet surfaces, and NPs were clearly separated from one another due to the presence of organic ligands formed on the NP surfaces. All NP samples showed broad peak characteristic of colloid NPs with a crystalline nature (Figure 5(b)). Patterns were similar to those of standard cubic bixbyite, which had no discernible SnO or SnO2 peak. Besides, the line-width of the (222) peak, Δ(2θ), was narrower for the NPs with D = 36 nm than D = 10 nm. These results reflected differences in crystallinity, size, defects, and strain in the NPs.
\n(a) Size distributions of ITO NPs with particle sizes (D) of 10, 20, and 36 nm. Inset images show TEM images of ITO NPs with different particle sizes. (b) XRD 2q-q pattern of ITO NPs with D = 10, 20, and 36 nm. Δ(2θ) indicates a line-width of the (222) peak [25].
TEM images of ITO NPs with D = 10 nm (a), 20 nm (b), and 36 nm (c) [25].
The absorption spectra of the NPs with different particle sizes are shown in Figure 7(a). Based on the Mie theory with frequency-dependent damping, the values of ne were approximately 1021 cm−3, and μe ranged from 21 to 37 cm2/V.s. The broadening of the absorption spectra was related to the quality factor (Q-factor) of the plasmonic resonance defined by the ratio of peak energy to spectral linewidth of the LSPR peak. This factor provided a good indication of weak electronic damping and efficient E-field generation. Q-factor values of LSPRs with D = 10, 20, and 36 nm NPs were 2.4, 3.3, and 4.5 respectively. The increase in particle size is expected for strong E-field enhancement on the NP surfaces. It was indicated that the Q-factor values in the LSPR peaks were attributed to the electronic and crystalline properties. On the other hand, the LSPR peak positions were independent of particle size.
\n(a) Absorption spectra of ITO NPs with different sizes comprising (a) 10 nm, (b) 20 nm, and (c) 36 nm. (d) LSPR peak energy as a function of particle size. A black line represents using Eqs. (4)–(6) [25].
The peak positions of LPRs generally depend on the particle size in the case of metal NPs. The size-dependent absorption spectra of spherical NPs can be calculated precisely using the full Mie equations. These equations can describe well the size effects of LSPRs in metal NPs as follows.
\nAn analytical solution to Maxwell’s equations describes the extinction and scattering of light by spherical particles. The electromagnetic field produced by a plane wave incident on a homogeneous conducting sphere can be expressed by the following relations [26]:
\nwhere k is the incoming wave vector and L are integers representing the dipole, quadrupole, and higher multipoles of the scattering. In the above equations, aL and bL are represented by the following parameters, composed of the Riccati-Bessel functions ψL and χL [26]:
\nHere, \n
Recently, plasmonic properties on oxide semiconductors have attracted much attention in the area of solar-thermal shielding. The purpose of our study is to apply the plasmonic properties of assembled films of ITO NPs. To date, IR optical responses have been investigated with regard to transmittance and extinction spectra of composites and films using oxide semiconductor NPs. IR shielding properties by transmittance and absorption properties have mainly been discussed [27, 28, 29, 30]. Reports concerning reflective performances in assemblies of NPs have yet to appear in spite of the desire for thermal shielding to cut IR radiation, not by absorption, but through reflection properties.
\nAssemblies of Ag and Au NPs can produce high E-fields through plasmon coupling between NPs in the visible range and are utilized in surface-enhanced spectroscopy [31, 32]. The high E-fields localized between NPs are very sensitive to interparticle gaps [33]. A gap length down to distances less than the size of a NP causes remarkable enhancements in E-fields. Surfactant- and additive-treated NPs are effective strategies that can be employed to obtain small interparticle gaps between NPs, which can be developed into one-, two-, and three-dimensional assemblies of NPs [34]. In particular, optical applications based on NPs have the benefit of large-area fabrications with lower costs to make NP assemblies attractive for industrial development.
\nIn this section, we report on the plasmonic properties of assembled films comprising ITO NPs (ITO NP films) and their solar-thermal applications in the IR range [35]. Both experimental and theoretical approaches were employed in an effort to understand the plasmonic properties of the NP films. The IR reflectance of the NP films was analyzed on the basis of variations in particle size and electron density. The investigation focused in particular on E-field interactions in order to determine how the NP films affected high IR reflectance. This behavior is discussed in terms of the physical concept of plasmonic hybridization, which further clarified the importance of interparticle gaps for high IR reflectance.
\nFigure 8(a) shows reflectance spectra of ITO NP films with different electron densities. The assembled ITO NP films were deposited on IR-transparent CaF2 substrates through a spin-coating technique. The spin-coating conditions comprised sequential centrifugation at (i) 800 rpm for 5 s, (ii) 2400 rpm for 30 s, and (iii) 800 rpm for 10 s. The fabricated NP films were then thermally treated at 150°C in air to evaporate the solvent. Reflectance was enhanced with increasing electron density and reached a value of ca. 0.6 in the NP film with ne = 1.1 × 1021 cm−3. Additionally, reflectance was dependent on film thickness (Figure 8(b)). Reflectance gradually increased with increasing film thickness and was then saturated in film thicknesses above 200 nm. As a result, it is necessary to use NPs with high electron density in order to obtain NP films with high IR reflectance.
\n(a) Reflectance spectra of ITO NP films with different electron densities of 1.1 × 1021 cm−3 (○), 8.7 × 1019 cm−3 (□), and < 1019 cm−3 (Δ). (b) Reflectance as a function of NP film thickness of ITO NP films with different electron densities.
Figure 9(a) shows reflectance spectra of ITO NP films with different particle sizes. Reflectance gradually increased with increasing particle size, which was dependent on NP film thickness (Figure 9(b)). That is, increasing in particle size contributed to obtain high IR reflectance. Highly efficient solar-thermal shielding played an important role in controlling electron density and particle size. We found that the high IR reflectance was closely related to plasmon coupling between the NPs in the NP films as follows.
\n(a) Reflectance spectra of ITO NP films with different particle sizes of 36 nm (○), 20 nm (□), and 10 nm (▵). (b) Reflectance as a function of NP film thickness of ITO NP films with different particle sizes.
Figure 10(a) shows experimental and theoretical absorption spectra of ITO NPs dispersed in toluene. The theoretical data was simulated using the finite-difference time-domain (FDTD) method and was close to the experimental data. We observed the formation of a strong electric field (E-field) on the NP surface (inset of Figure 10(a)). The relationship between the E-field and photon energy was further investigated, as shown in Figure 10(b–d). The E-field on the NP surface increased with increasing photon energy. A high E-field was obtained at an LSPR peak position of 1.8 μm. The LSPRs of ITO NPs produced the strong E-field on the NP surface.
\n(a) Absorption spectra of ITO NPs: Experimental (open circles) and simulated data (solid line). Inset indicates an electric field distribution on the NP surface obtained by the FDTD simulation. Cross-section field distributions at 1.2 μm (b), 1.5 μm (c), and 1.8 μm of the NPs.
We evaluated the optical properties of ITO NP films from the viewpoint of electrodynamic simulations based on the finite-difference time-domain (FDTD) method (Figure 11(a)). The modeled NP layer was assumed to have a hexagonally close-packed (HCP) structure with an interparticle distance (r) of 2 nm along the in-plane (x-y) and out-of-plane (y-z) directions (Figure 11(b and c)). The modeled sample was illuminated with light directed in the z direction from the air side. The E-field was parallel to the x direction. The refractive index (real part: 1.437) of capric acid was used for the medium between the NPs. The dielectric functions of the ITO NPs were obtained from the parameter fitting for the absorption spectra. Figure 11(a) shows the reflectance spectra of ITO NP layers with different particle sizes (D) of 10, 20, and 36 nm. The number of the NP layer was set to the N = 20 NP layer. Reflectance clearly enhanced with increasing particle size, which appeared as a result of three-dimensional assemblies of ITO NPs, and it was suggested theoretically that increasing particle size contributed to the reflective-type thermal shielding in the IR range.
\n(a) Simulated reflectance spectra of ITO NP layers at different particle sizes (D). A number of NP layer (N) was set to N = 20 NP layers. (b) and (c) indicate structural diagrams of a simulated NP layers along the in-plane (x-y) and out-of-plane (x-z) directions, respectively. The modeled structure was assumed to have a HCP structure with an interparticle distance (r) of 2 nm and was illuminated with light directed in the z direction from the air side. The E-field was parallel to the x direction.
Plasmon coupling between NPs produces large enhancements of E-fields at interparticle gaps. We typically investigated the E-field distributions at peak-II (0.60 eV) and peak-I (0.208 eV) for a 20 NP layer with D = 36 nm. Figure 12(a and b) shows SEM images of ITO NP films (D = 36 nm) along the in-plane and out-of-plane directions, revealing that the NPs had close-packed structures along both directions. Figure 13 shows the E-field distributions along the x-z directions. For peak-I, the E-field between the NPs was strongly localized along the x direction when an electric field of light was applied along this direction. In contrast, peak-II displays E-fields along the diagonal directions in the x-z plane in addition to those along the x direction. A difference in the E-field of peak-I and peak-II was clearly found. The FDTD simulations revealed that the two types of reflectance peaks had different mechanisms of plasmon excitations. Therefore, it was indicated that different E-field distributions between the NPs played an important role in producing the IR reflectance in the IR range.
\nSEM images of an ITO NP film along the in-plane (a) and out-of-plane (b) directions.
Images of the E-field distributions and charge vectors at peak-I and peak-II along the x-z directions. Regions delimited by white circles were positioned in the respective bottom parts. An E-field was applied along the x direction. Light was incident along the z direction from the air side.
Optical properties of carrier- and size-dependent LSPRs were investigated using dopant-controlled ITO NPs. From systematic correlations between LSPR excitations and electron density, plasmon damping of ITO NPs was closely related to electron-impurity scattering, which was effective with high ne values greater than 1020 cm−3. That is, the role of electron carriers in ITO NPs could enhance LSPRs with simultaneous damped plasmon excitations. Changes in particle size also affected the LSPRs in ITO NPs. Increasing particle size altered the magnitude and peak splitting of the resonant reflectance, which covered a wide IR range. As a result, the carrier and size control of ITO NPs led to high solar-thermal shielding. The origin of the high IR reflectance of ITO NP films was clarified by electrodynamic simulations (FDTD). We found that the E-field distributions between the NPs along the in-plane and out-of-plane directions played key roles in producing the high IR reflectance. Control of electron carrier and particle size revealed important aspects that should be considered in the area of structural design when fabricating thermal-shielding materials.
\nThis research was supported in part by a grant from JST A-Step (No. VP30218088667) and for Grant-in-Aids for Scientific Research (B) (No. 18H01468).
\nThe authors declare no competing financial interest.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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