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- Copyright © 2020 Anna Bednarek et al. 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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Abstract
Hindawi Journal of Oncology Volume 2020, Article ID 7267083, 11 pages https://doi.org/10.1155/2020/7267083 Review Article Limitations of Systemic Oncological Therapy in Breast Cancer Patients with Chronic Kidney Disease 1 1 2 Anna Bednarek , Joanna Mykała-Cies´la, Katarzyna Pogoda , 2 2 1 Agnieszka Jagiełło-Gruszfeld , Michał Kunkiel , Mateusz Winder , and Jerzy Chudek Department of Internal Diseases and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice 40-027, Poland Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warszawa 02-034, Poland Correspondence should be addressed to Anna Bednarek; annabednarekmd@gmail.com Received 17 January 2020; Revised 9 April 2020; Accepted 23 April 2020; Published 18 May 2020 Academic Editor: Ozkan Kanat Copyright © 2020 Anna Bednarek et al. )is 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. Breast cancer is the most common malignancy, affecting middle-age and older women frequently suffering from other chronic diseases, including chronic kidney disease. )e risk of breast cancer development in women on renal replacement therapy (peritoneal dialysis and haemodialysis) is higher than in the general population. Chronic kidney disease does not limit surgical treatment or radiotherapy; however, it affects the pharmacokinetics of drugs used in the systematic treatment to a different extent, increasing their toxicity and the risk of adverse drug reactions. )is article summarizes the current knowledge (published studies accessed through PUBMED) on drugs used in chemotherapy, hormone therapy, anti-HER2 drugs, CDK4/6 inhibitors, PARP inhibitors, and immune therapy in breast cancer patients undergoing dialysis. We discuss the data, the optimal choice of the chemotherapeutic protocol, and the administration of drugs in a specific time relation to the haemodialysis session to ensure the most effective and safe treatment to breast cancer patients. development, which results in a higher incidence of breast 1. Introduction cancer in this population [3, 4]. )e incidence of chronic kidney disease (CKD) and its )e US Renal Data System indicates an increased risk of terminal stage—end-stage kidney disease (ESKD)—in the cancer, including breast cancer, among HD patients. In the population increases due to the prolongation of human life. years 1996–2009, 3552 HD women were diagnosed with breast An increase in the number of patients with ESKD treated cancer, that is, 42% more than in the general population [5]. In with renal replacement therapy is observed in the group of addition, a larger half (52.9%) of patients starting anticancer 60 years old and older. Haemodialysis (HD) is the primary treatment had abnormal renal function (eGFR< 60 m/min/ 1.73 m method of renal replacement therapy that has been used ) and required anticancer drug dose adjustments. since the early 1960s. )e number of patients on dialysis However, the lack of an appropriate drug dosage adjustment differs substantially across countries and regions and is was related to a reduced overall survival [6]. affected by access to health care [1]. )e number of HD Breast cancer is the most common malignancy in women patients worldwide exceeds 1 million worldwide and is worldwide, also in Poland (22% of malignancies in women). steadily growing. In Poland, this method is used for more Globally, every eighteenth woman develops breast cancer than 20,000 patients yearly, including about 9,000 women over a lifetime [7, 8]. CKD is not listed among the most [2]. )e slowly improving survival of patients treated with important risk factors for breast cancer, such as age, family renal replacement therapy increases the chance for cancer history of breast cancer (BRCA1 and BRCA2 mutations), 2 Journal of Oncology early menarche, late menopause, late pregnancy, long-term Orally administered tamoxifen has an almost 100% hormone replacement therapy (HRT), exposure to ionizing bioavailability [11]. )e molecule has high lipophilicity, and radiation, and some benign breast proliferative diseases more than 95% of the drug is transported bound to proteins. [2, 9]. Tamoxifen is metabolised by cytochrome P450 (CYP2D6 )e management of breast cancer depends on the stage isoform) [12]. )e main metabolites of tamoxifen are 4- of cancer and includes surgery, which may be preceded or hydroxy tamoxifen and N-desmethyltamoxifen. More than followed by chemotherapy or radiation therapy, or both. 60% of the drug dose is excreted unaltered in the faeces and Oestrogen and progesterone receptor-positive cancers are only 9–14% with the urine. )e plasma level of tamoxifen often treated with hormone-blocking therapy over courses remains constant for 3-4 weeks when the daily supply is of several years. Monoclonal antibodies to HER2 (human 20–40 mg once a day. )e half-life of tamoxifen is 5–7 days, epidermal growth factor receptor 2) receptors are used in whereas of its metabolite N-desmethyltamoxifen—13 days. patients with overexpression of these receptors on cancer When the daily dose is 20 mg, serum concentrations of cells [9, 10]. Advanced CKD (chronic kidney disease), HD, tamoxifen range from 164 to 494 ng/ml, and the mean and peritoneal dialysis (PD) do not limit the possibility of concentration of N-desmethyltamoxifen is 226± 77 ng/ml surgical treatment and radiotherapy but have a significant [13]. )e pharmacokinetics of tamoxifen depends on the age impact on the pharmacokinetics of cytotoxic agents and of the patient [14], but even in the case of older patients, it is other drugs used in oncological therapy due to the reduc- not recommended to reduce the dose of tamoxifen. tion/loss of renal clearance of drugs and their metabolites. Langenegger et al. [11] described the use of tamoxifen in )e elimination of drugs during HD and PD depends on the an HD patient with breast cancer. )is therapy was well diffusion that occurs through the semipermeable membrane tolerated by the patient. )e plasma concentrations of the and is limited by the protein binding potency. drug and its metabolite N-desmethyltamoxifen in dialysis Drugs with a low molecular mass (MM), up to 500 Da, patients were similar to those observed in non-HD patients. and poorly binding to proteins are easily removed through a )erefore, tamoxifen pharmacokinetics does not force a dialysis membrane and therefore should not be used im- modification of the drug dose in patients with CKD/ESKD, mediately before the HD session (cyclophosphamide, 5- including the dialysed. Reducing the dose might limit the fluorouracil, and capecitabine). Modern HD techniques effectiveness of the treatment [15, 16]. Because of its high using synthetic highly permeable membranes (high-flux) lipophilicity, the drug may be administered even shortly and high ultrafiltration (haemodiafiltration) make it possible before the HD session. to remove significantly larger molecules with a MM greater than 1500 Da. However, the purification process is carried 2.2. Anastrozole. Aromatase inhibitors (anastrozole, letro- out only during 3 dialysis sessions per week. zole, and exemestane) are used in early and metastatic breast )is review aims to summarize the current knowledge on cancer. drugs used in adjuvant, neoadjuvant and palliative chemo- Anastrozole (MM: 293.4 Da) is a nonsteroidal aromatase therapy, hormone therapy, anti-HER2 drugs, CDK4/6 in- inhibitor. )ere is an increased frequency of calcium and hibitors, PARP (poly ADP-ribose polymerase) inhibitors, and vitamin D deficiency in patients with CKD/ESKD and at the immune therapy in breast cancer patients undergoing HD risk of renal osteodystrophy development. )erefore, bone and PD. We discuss the data on how to optimally choose the mineral density (BMD) should be measured and vitamin D chemotherapeutic protocol and administer the drugs in or its active metabolites therapy should be considered specific time relation to the HD procedure in this specific necessary before the initiation of the treatment with aro- group of patients to ensure the most effective and safe matase inhibitors [11]. treatment of breast cancer. )e benefits of systemic ther- Forty percent of the drug is bound to plasma proteins. As apy—potential improvement in progression-free survival and much as 85% of anastrozole is metabolised by the liver and overall survival—should be weighed against an increased risk excreted into the faeces, while only about 11% is excreted by of toxicity as well as deterioration of the health-related quality the kidneys. Anastrozole half-life is long (41 h) [11]. of life. According to Langenegger et al. serum anastrozole con- )is review was based on literature search in PUBMED centrations in HD patients are similar to those seen in (published before September 2019), concerning descriptions patients with normal renal function, and the drug itself is of the cases of HD patients with breast cancer, included data well tolerated [11]. )e results of this study indicate that in on the pharmacokinetics of chemotherapeutic agents in the case of CKD/ESKD patients, anastrozole may be used in other than breast cancers malignancies, and comprised the same dose as in patients with preserved kidney function. information given in the summaries of product character- Due to the low MM and moderate affinity with plasma istics, including the results of nonpublished studies. proteins, the drug should be taken after the HD session. 2. Hormone Therapy 2.3. Letrozole. Letrozole (MM: 285.3 Da) is an aromatase 2.1.Tamoxifen. For over 20 years, tamoxifen (MM 371.5 Da) inhibitor that is converted in the liver into an inactive has been widely given in early and metastatic breast cancer metabolite carbinol (isoenzymes: 3A4 and 2A6 of cyto- chrome P450). )ere is no need to reduce the dose ad- patients with expression of oestrogen (ER) and/or proges- terone (PgR) receptors [2]. ministered to older women [11]. Journal of Oncology 3 Summary of drug characteristics informs that it is un- last-line of hormone therapy until the safety date is available necessary to adjust the dosage for CKD patients whose in CKD/ESKD patients. Except for anastrozole that should be administered after creatinine clearance (CC) is greater than 30 ml/min. No dosage data are available for patients whose CC< 30 ml/min. a dialysis session, all the drugs have high affinity to proteins )ere is a single report on treating an HD breast cancer and are not eliminated by dialysis. )erefore, thereis no need patient with letrozole (with lapatinib) [17]. )e therapy, to specify any time relation to the dialysis session. In the case without dose reduction, was tolerated well. of fulvestrant, due to the intramuscular way of adminis- tration, the drug should be administered on nondialysis days. 2.4. Exemestane. Exemestane (MM: 296.4 Da) strongly binds with proteins (90%) and is inactivated by the liver 2.7. Cyclin-Dependent Kinase 4/6 (CDK4/6) Inhibitors. (metabolites are not biologically active). Only 1% of the CDK4/6 inhibitors added to hormone therapy significantly administered dose is excreted unaltered into the urine. In improve outcome in metastatic breast cancer patients. All patients whose CC< 30 ml/min. AUC (area under the three registered drugs (ribociclib, palbociclib, and abema- concentration curve) was twice as large as in healthy vol- ciclib) are small protein-bound molecules metabolised in the unteers. No dosage and safety data are available for patients 2 liver (CYP3A4) and excreted into faeces. )e pharmaco- whose eGFR <30 ml/min/1.73 m and those on renal re- kinetic profiles do not justify a dose reduction of these drugs placement therapy. Taking into account the exemestane in CKD patients. However, the pharmacokinetic and safety profile, no dose adjustment is required for CKD patients. data in “renal patients” are not available yet. However, due to the lack of data on pharmacokinetics and It was shown that CKD4/6 inhibitors may have some safety in dialysis patients, this drug should be used with nephroprotective activity. )e targeted inhibition of the caution, only when other therapeutic options are not CDK4/6 pathway was shown to ameliorate the kidney injury available [18]. induced by cisplatin [21]. It should be mentioned that in about 40% of individuals, therapy with abemaciclib is associated with a reversible 2.5.Fulvestrant. Fulvestrant is a selective oestrogen receptor increase in serum creatinine concentration greater than 50% degrader (SERD) with an MM of 606.9 Da highly (99%) over the baseline level [22]. Abemaciclib was shown to bound to plasma lipoproteins, slowly metabolised via the inhibit renal tubular secretion of creatinine without changes same pathways as endogenous steroids in the liver and in the measured glomerular filtration rate and the structural metabolites excreted into faeces. It is used in the metastatic markers of kidney tubular injury (serum and urinary neu- setting. Its biological half-life is estimated at about 40 days. trophil gelatinase-associated lipocalin and urinary kidney )ere is no published pharmacokinetic and safety data in injury molecule-1) [23]. dialysis patients concerning the use of fulvestrant. )e negligible role of the kidney in the elimination of fulvestrant 3. Chemotherapy suggests its use in unchanged doses. )is drug should be used with caution in severe CKD and ESKD patients [19]. Standard adjuvant and neoadjuvant chemotherapy consists of anthracycline-based multidrug regimens (doxorubicin, DOX or epirubicin, EPI with cyclophosphamide, CTX) and 2.6. Megestrol Acetate. Megestrol acetate (MM: 384.5 Da) is taxanes (docetaxel, DXL and paclitaxel, PXL), mainly in a synthetic progestin with the same physiologic effects as patients with a higher risk of recurrence. )ese drugs can be natural progesterone with antianorexic and anticachectic used also in advanced breast cancer. Other drugs for early or effect used in the therapy of progressive breast cancer for metastatic breast cancer are 5-fluorouracil (5-FU), capeci- many years. )e drug has a high affinity to albumins and tabine, methotrexate (MTX), vinorelbine (VRB), carbopla- therefore is not excreted by the kidneys. It is slowly tin, cisplatin (DDP), and gemcitabine [2, 10]. metabolised by the liver, and its metabolites are excreted into faeces. )e safety of this drug in dialysis patients with protein-wasting was shown in numerous trials [20]. )ere 3.1. Anthracyclines. Doxorubicin (DOX) (MM: 543.5 Da) were few reported adverse drug reactions (suppressed and epirubicin (EPI) (MM: 543.5 Da) are removed mostly by cortisol levels, thrombophlebitis, and vaginal bleeding). the liver and in a lesser degree excreted by the kidneys (15% Based on this experience, megestrol acetate can be recom- and 10%, respectively). )e AUC for DOX in HD patients is mended in the therapy of metastatic breast cancer. approximately 1.5 to 3 times higher than in patients with In conclusion, taking into consideration the afore- normal kidney function, and the HD removal of the drugs mentioned data, giving adjuvant oestrogen deprivation was low [24]. )e impaired metabolism of DOX in patients therapy to breast cancer CKD/ESKD patients is considered with CKD is related to diminished activity of aldo-keto quite safe. Due to limited safety data, patients with CKD/ reductase in the kidney, an enzyme involved in the inacti- ESKD should receive tamoxifen or anastrozole or letrozole vation of the drug by C13 carbonyl reduction of doxorubicin rather than exemestane. In patients with metastatic disease to its inactive hydroxy metabolite doxorubicinol [25, 26]. anastrozole, letrozole and megestrol acetate are considered For this reason, a 20% reduction of the DOX dose in safer than exemestane. Fulvestrant may be considered as the patients with CKD seems reasonable. A dose reduction in 4 Journal of Oncology dialysis patients is not recommended [27]. )ere are no data amount, they are excreted into the urine [28]. )e phar- on EPI pharmacokinetics in HD patients. In the case of macokinetics of a 135 mg/m dose of PXL in a 3-hour in- patients with CC< 30 ml/min, a reduced dose should be travenous infusion in an HD patient was similar to that in considered; however, the number of studies on the effec- patients with normal renal function [33]. )e description of tiveness of a reduced dose is very limited [28]. Gori et al. [29] DXL pharmacokinetics is based on a single HD patient [34], presented a case report of a 51-year-old HD patient with indicating no effect of an impaired renal function on the breast cancer. In the case described, EPI therapy was well elimination process. )ese data indicate the possibility of tolerated. No leukopenia, thrombocytopenia, and car- treating dialysis patients with the unaltered dosage of these diotoxicity were observed (ejection fraction—LVEF—was drugs. Currently, in breast cancer patients, PXL is usually stable). administered in a dose of 80 mg/m every week. )e CKD appears to worsen the cardiotoxicity of EPI. Russo pharmacokinetics data for this dose are not available. et al. described a 12-month follow-up indicating an in- However, as the pharmacokinetics of a larger dose of PXL is creased risk of total anthracyclines, taxanes, and trastuzu- not affected by the kidney function, the alterations are not mab cardiotoxicity in patients with an estimated glomerular expected. filtration rate (eGFR) <60 ml/min/1.73 m . In this group of PXL was well tolerated by HD patients. Watanabe et al. described safe and effective use of PXL in a 40-year-old HD patients, cardiac events were 52% more common than in those with eGFR ≥60 ml/min/1.73 m (38% vs. 25%) [30]. woman [33]. Good tolerance of DXL was also demonstrated in a Because of the MM and no data on HD removal, DOX 72-year-old HD patient with prostate cancer [34]. )e authors and EPI administration is recommended after the HD proposed the use of DXL at an initial dose of 65 mg/m , and its session or on nondialysis days. possible increase when the drug tolerance was good. 3.2. Cyclophosphamide. Cyclophosphamide (CTX) (MM: 3.5. Anthracycline- and Taxane-Based Regimens. )e results 261.1 Da) is excreted in 50% to 70% by the kidneys within 48 of the studies suggest that the AC⟶ T (doxorubicin and hours, 32% of which is excreted in an unaltered form [24]. cyclophosphamide followed by docetaxel) regimen can be used Nephrotoxicity is a very rare side effect (CKD is a risk in CKD/ESKD (including HD) patients with breast cancer, with factor). When excreted in the urine, CTX metabolites the already mentioned 20–25% dose reduction of DOX in HD damage the epithelium of the urinary tract—especially in the patients. )ere are a lack of data enabling evaluation/compar- bladder. )erefore, haemorrhagic cystitis is the most ison of the efficacy of these treatments in individuals on renal common dose-dependent adverse drug reaction to CTX replacement therapy with nonrenal patients. [31]. )e number of studies concerning CTX treatment in 3.6. 5-Fluorouracil (5-FU). 5-FU (MM: 130 Da) is a py- dialysis patients is very limited. In the available literature, a rimidine antimetabolite. After intravenous administration, case report of a 48-year-old HD woman with breast cancer the half-life of 5-FU is about 16 minutes and depends on the was described. In the case, the maximum plasma concen- dose of the drug. Only about 15% of the 5-FU dose is ex- tration of CTX was 49 μg/ml, and the in vivo half-life was creted unaltered into the urine [28]. 67 h [24]. It is believed that typical doses of 5-FU may be given to CTX is removed during HD. It should, therefore, be ESKD patients after the HD session or on nondialysis days. administered after HD or on nondialysis days. A 25% dose reduction is recommended [27]. 3.7. Capecitabine. Capecitabine (MM: 359.3 Da) is a pro- drug converted to 5-FU. Capecitabine and its active me- 3.3. Two-Drug Regimens (AC/EC). AC regimen with a tabolites are excreted primarily by the kidneys, i.e., 96% of 20–25% reduction of the DOX dose can be considered safe in the administered dose is detected in the urine. )e literature patients with CKD/ESKD, including HD patients [27]. on the treatment of HD patients with capecitabine is limited. Attention should be paid to the increased risk of car- Jhaveri et al. described 12 patients with severe CKD or ESKD diotoxicity. Due to the lack of EPI pharmacokinetic data, the (CC <30 ml/min), among them two cases of HD patients EC regimen is not recommended for patients with ESKD were treated with capecitabine. Its toxicity was acceptable and on HD. )ere are no data available to evaluate/compare (low). Patients with ESKD were treated with a reduced dose the efficacy of these treatments in ESKD patients. (on average, up to 55% of the standard dose). Despite the When using two-drug regimens in HD patients, che- dose reduction, a satisfactory response to the treatment was motherapy should be administered on nondialysis days. observed. )e pharmacokinetics of the drug was evaluated in this study. )e authors suggested the reduction of the drug 3.4.PaclitaxelandDocetaxel. Paclitaxel (MM: 853.9 Da) and dose by half [35]. )e low number of observations in ad- its semisynthetic analogue—docetaxel—(MM: 807.9 Da) are dition to the dose reduction suggests the need for strict microtubule antagonistic drugs. Both drugs strongly bind to monitoring of the drug toxicity (myelosuppression, hand- proteins (>90%), primarily with albumin and alpha-1-gly- foot syndrome, and diarrhoea) after therapy initiation. )e coprotein [32]. )ey are metabolised in the liver by the low MM of the drug and the lack of protein binding preclude cytochrome P450 and excreted into the bile. In a small capecitabine administration before the HD session. Journal of Oncology 5 with urine as an unchanged drug (15–75%) [44, 45]. 3.8. Gemcitabine. Gemcitabine (MM: 263.2 Da) is quickly metabolised in the liver and the kidneys, with its renal fil- Nephrotoxicity precludes its use in CKD patients; however, it may be used in dialysis ESKD patients [46]. )e feasibility tration not exceeding 10%, as only 10% is bound to plasma proteins. Kidneys, as well as HD, remove the main non- of cisplatin-based regimens was confirmed in nonbreast cytotoxic metabolite of gemcitabine—difluorodeoxyuridine cancer patients [47, 48]. )ese data clearly show that CDDP (dFdU). doses 50–80 mg/m are quite well tolerated when starting the No significant toxicity and pharmacokinetic alterations HD session within 30 min postinfusion. However, there are of gemcitabine and dFdU were reported in CKD and ESKD no data concerning CDDP safety and efficacy in dialysed patients receiving doses of up to 1200 mg/m compared to breast cancer patients [49, 50]. patients with a normal kidney function. A dose reduction of gemcitabine in CKD/ESKD patients is not required. )e HD 3.11. Methotrexate (MTX). Methotrexate (MM: 454.4 Da), session should start not earlier than 6–12 hours after the which is a folic acid derivative, belongs to the group of infusion of chemotherapy [36]. )ere are no data concerning antimetabolites. MTX is eliminated primarily by the kidneys. toxicity and efficacy in breast cancer patients with ESKD. )e excretion depends mainly on the dose and route of the drug administration. After intravenous administration, 3.9. Carboplatin. Carboplatin (MM: 371.3 Da) is a second- about 90% of the dose is eliminated unaltered from the body generation of less nephrotoxic platinum analogues. Ad- within 24 hours. No more than 10% of the dose is excreted ministered intravenously, carboplatin is not avidly protein into the bile. )e MTX metabolite of the highest importance bound initially, but the majority of the drug becomes protein is 7-hydroxymethotrexate produced in the liver with alde- bound within 24 h, and 55–70% of the drug is excreted by the hyde oxidase. )e MTX half-life in the terminal elimination kidney in the first 24 h [37]. According to the summary of phase is between 3 and 10 hours in patients treated with low product characteristics, carboplatin may be used in patients doses of MTX (less than 30 mg/m ), whereas in the case of with CC> 20 ml/min, but the dose has to be reduced when patients receiving high doses of MTX, the terminal elimi- CC is below 60 ml/min to prevent excessive myelotoxicity nation half-life is 8 to 15 hours. Competition between MTX [38]. In so-called “renal patients,” the dose should be cal- and other drugs excreted with the same mechanism may culated according to the Calvert formula for the fixed AUC increase serum levels of this drug. Nonsteroidal anti-in- target [39]. However, not recommended by the manufac- flammatory drugs may interfere with MTX renal clearance turers, carboplatin in a reduced dose may be used in dialysis and lead to toxic symptoms of the therapy. )e common patients. Few reports describe nonbreast cancer patients adverse drug reactions (ADRs) of high doses of MTX used in treated with carboplatin with a dose calculated according to haematology (up to 6 g/day) include haematuria and acute the Calvert formula with CC taken as zero, corrected for the kidney injury. During MTX treatment, its metabolites may time interval between the infusion and the planed HD or PD precipitate in the kidney tubules. )erefore, intensive fluid session [40, 41]. Recently, AIOM guidelines suggest calcu- therapy and alkalization of the urine to pH 6.5–7.0 are lation of a carboplatin dose AUC × 25 mg in HD patients recommended during the treatment, e.g., with sodium bi- [27]. carbonate (5 tablets × 625 mg every three hours) or acet- Both the HD and peritoneal procedures should be azolamide (not recommended in CKD). High doses of MTX, performed within 12–18 h after the carboplatin infusion i.e., above 1000 mg/m , may cause acute renal failure, which before carboplatin has become bound to proteins and not worsens the elimination of the drug from the body. )e dialyzable. Hiraike et al. demonstrated that the standard incidence of ADRs increases with the dose [51]. dose of carboplatin-targeted AUC was determined based on )e doses used in the therapy of breast cancer (CMF the Calvert formula, without any correction, and maintained regimen) are much lower. However, Langleben et al. de- quite normal pharmacokinetics, if the HD began an hour scribed the effects of severe toxicity following the first ad- after the dose administration [42]. In the PD patient ministration to a patient with breast cancer [52]. )e (CAPD), 20% of the dose is cleared via the dialysate, while reduction of toxicity can be achieved using daily high-flux the half-lives of carboplatin are double compared to patients dialysis [53]. with normal renal function [43]. )e use of MTX in ESKD patients is not recommended if Optimally, the carboplatin-based chemotherapy should there is any other treatment option. In HD patients, the dose be administered on dialysis days, shortly before the session has to be reduced by 75% [27]. to eliminate the cell breakdown products. However, for organisational reasons, the current guidelines recommend 3.12. CMF Regimen (CTX, MTX, and FU). )is chemo- the administration of carboplatin on nondialysis days [27]. therapy regimen is not recommended due to the poor tol- erance of MTX by CRF and HD patients. 3.10. Cisplatin (CDDP). CDDP (MM: 300 Da) is less fre- quently used than carboplatin platinoid in the palliative therapy of triple-negative breast cancer resistant to taxanes 3.13. Vinorelbine (VRB). Vinorelbine (778.9 Da) is removed and anthracyclines [44]. )e drug strongly binds to from the body mainly by the liver. Only 8% of the ad- protein and is slowly eliminated from the circulation ministered dose is excreted unaltered by the kidneys [54]. (T1/2 = 58.5–73 h) [45] mainly by the kidney and excreted )ere are no data on pharmacokinetics in CKD/ESKD and 6 Journal of Oncology HD patients. )ere is a single report of VRB administration have not been fully assessed. Because of their cardiotoxicity, in a HD patient in a weekly dose of 25 mg/m , resulting in anthracyclines and trastuzumab should not be used si- severe leukopenia with pneumonia. )e authors reduced the multaneously. Due to the nonlinear elimination of the drug dose by 50% and that was well tolerated. However, it is (catabolism), the total clearance increases along with the uncertain whether the efficacy of the therapy was main- decrease of its concentration. )erefore, the half-life of tained. According to AIOM, a reduction of 25–33% should trastuzumab cannot be easily determined. T1/2 falls together be considered [27]. with a decrease in the concentration between successive In patients with metastatic disease and severe CKD or doses [56]. ESKD, the VRB + DOX, a rarely used regimen, should be Available data do not indicate the need for a dose ad- debated in breast cancer treatment only when other ther- justment in patients with renal dysfunction [57]. It should be apies are no longer available. stressed that pharmacokinetic studies of this drug did not include patients with ESKD. Only two observations on treating HD patients with trastuzumab are available in the 4. Anti-HER2 Therapy: Tyrosine literature [57, 58]. In both cases, a clinical response was Kinase Inhibitors obtained with good drug tolerance. )e authors pointed out 4.1. Lapatinib. Lapatinib (MM: 851 Da) is a dual tyrosine that the therapeutic concentration of trastuzumab was kinase inhibitor that interrupts the HER2 and EGFR reached, but no data were collected on the level of trastu- pathways registered for therapy of metastatic disease in zumab in the blood. Another case report is available on a 64- combination with capecitabine. It highly bounds to albumin year-old HD patient treated with trastuzumab at a dose of and undergoes extensive metabolism, primarily by CYP3A4 4 mg/kg—a loading dose—followed by 2 mg/kg every 7 days and CYP3A5 to a variety of oxidized metabolites excreted for one year. )e data on the pharmacokinetics of trastu- with the faeces. As lapatinib is not eliminated by the kidneys zumab were collected during the first course of the treat- and is highly bound to plasma albumin, HD is not expected ment. )e maximum plasma concentration was 190 mg/l at a to enhance the elimination of the drug. A single case report dose of 2 mg/kg, and the maximum plasma concentration suggested good tolerance of lapatinib with letrozole in an ranged from 75 to 163 mg/l. )e plasma concentration of HD female with metastatic disease [17]. trastuzumab did not decrease during HD [58]. It was constant and reached more than 20 mg/l, and it was within the therapeutic range recommended for patients treated for 4.2. Neratinib. Neratinib (MM: 557 Da) is a tyrosine kinase breast cancer. )e collected data show that trastuzumab is inhibitor that together with their active metabolites irre- not eliminated from the blood during HD due to its high versibly binds to EGFR, HER2, and HER4 reducing auto- MM (145 kDa). )e pharmacokinetics of the drug, in this phosphorylation of the receptors, and, as a consequence, case, was similar to that observed in patients with a normal blocks signal transduction. It is used in the extended ad- renal function. juvant therapy for early-stage breast cancer with HER2 In conclusion, the pharmacokinetics of trastuzumab in overexpression, after a 1-year therapy with trastuzumab the treatment of breast cancer in HD patients does not [55]. )e drug strongly binds to proteins (99%) and is undergo significant changes, but it may, however, imply an eliminated by the liver and excreted (metabolites) mostly increased risk of cardiotoxicity, which should be verified in with the faeces (97%). Episodes of acute renal failure were further studies. For this reason, the first control echocar- reported as a consequence of diarrhoea and vomiting with diography should be performed earlier, 6–9 weeks after dehydration [55]. therapy initiation. )e pharmacokinetics of the drug was not studied in dialysis patients, yet, but available data do not indicate the need for dose adjustment in patients with renal dysfunction. 5.2. Trastuzumab Emtansine (T-DM1). T-DM1 is an anti- )e safety data in kidney patients are not accessible. body-drug conjugate consisting of the monoclonal anti- body—trastuzumab—covalently linked to a microtubule 5. Anti-HER2 Therapy: Monoclonal Antibodies inhibitor—emtansine (DM1)—indicated for the treatment and Conjugates of patients with HER2-positive, unresectable, locally ad- vanced, or metastatic breast cancer who had previously Passive immunotherapeutic strategies in the management of received trastuzumab and a taxane, separately or in com- breast cancer overexpressing HER2 include the use of bination. It is recently recommended also in patients with trastuzumab (recombinant monoclonal humanized IgG1 residual disease (non-pCR) after neoadjuvant therapy. HER2 blocker antibody) and, more recently, pertuzumab T-DM1 catabolites (DM1, Lys-MCC-DM1, and MCC-DM1) (recombinant monoclonal humanized IgG1 antibody that are mainly excreted by the liver (in bile) with a minimal blocks HER2 receptor dimerization) and T-DM1 (trastu- elimination with urine due to high MM (148 kDa) [59]. )e zumab emtansine conjugate). effect of GFR on T-DM1 clearance was not clinically relevant [60]. )e pharmacokinetics of the drug was not studied in dialysis patients, yet. )e safety data in kidney patients are 5.1. Trastuzumab. Trastuzumab treatment is generally well not available. However, increased cardiotoxicity can be tolerated; however, it is associated with an increased risk of expected, similarly to its component–trastuzumab. cardiac dysfunction. Nevertheless, its long-term side effects Journal of Oncology 7 Table 1: Summary of pharmacokinetics and safety of systemic therapeutics for breast cancer in haemodialysis patients. Administration in Molecular Dose reduction in relation to Drug Elimination Safety Literature mass (Da) haemodialysis patients haemodialysis session 60% with faeces, Tamoxifen 371.5 9–14% with Not indicated Safe Before HD [11–16] urine 85% with faeces, Anastrozole 293.4 Not indicated Safe After HD [11] 11% with urine 90% with urine Letrozole 285.3 Not specified No data NA [17] (metabolites) Exemestane 296.4 1% with urine Not indicated Safe NA [18] <1% with urine, Fulvestrant 606.9 90% with faeces Not indicated No data Nondialysis days [19] (metabolites) 8% with urine, Megestrol acetate 384.5 90% with faeces Not indicated Safe NA [20] (metabolites) 69% with faeces, Ribociclib 434.5 Not specified No data NA [21] 23% with urine 74% with faeces, Palbociclib 447.5 Not specified No data NA [21] 18% with urine 81% with faeces, Abemaciclib 506.6 Not specified No data NA [21–23] 3% with urine 75% with faeces, Docetaxel 807.9 Not specified Safe Before or after HD [24,32,34] 6% with urine 1.3–12.6% with Paclitaxel 853.9 Not specified Safe Before or after HD [33,43,50] urine Recommended dose Increased risk of Doxorubicin 543.5 15% with urine After HD [25,26] reduction by 20% cardiotoxicity Recommended dose Increased risk of Epirubicin 543.5 10% with urine reduction After HD [29] cardiotoxicity (creatinine> 450µmol/l) Recommended dose Almost all with Increased risk of Carboplatin 371.3 reduction (CC< 60 ml/ Nondialysis days [37–43] urine myelotoxicity min) Increased risk of nephrotoxicity in CKD Almost all with Nonspecified in dialysis Cisplatin 300 patients. Increased risk After HD [44–50,71] urine patients of myelotoxicity in dialysis patients 50–70% with Recommended dose Haemorrhagic cystitis Cyclophosphamide 261.1 After HD [24,27,31] urine reduction by 20% (CKD independent) 5-Fluorouracil 130.1 15% with urine Not indicated Safe After HD [27,28] Recommended dose Capecitabine 359.3 96% with urine Safe (limited data) Before HD [35] reduction by 50% Liver, kidneys 6–12 hours before Gemcitabine 263.2 Not recommended Safe [27,36] <10% HD Increased myelotoxicity in Methotrexate 454.4 90% with urine No data dialysis patients, high- After HD [27,52,53] dose nephrotoxicity in CKD Increased Probably necessary (up to Vinorelbine 778.9 8% with urine myelotoxicity (limited After HD [54] 50%) data) 2% with urine, >90% with Lapatinib 581.1 Not indicated Safe (limited data) NA [17] faeces (metabolites) 8 Journal of Oncology Table 1: Continued. Administration in Molecular Dose reduction in relation to Drug Elimination Safety Literature mass (Da) haemodialysis patients haemodialysis session 2% with urine, Neratinib 557 97% with faeces Not indicated No data NA [55] (metabolites) 44% with urine, Recommended 25% dose Olaparib 435.1 42% with faeces reduction (CC< 50 ml/ No data NA [62,64] (metabolites) min) Recommended 25% dose 50% with urine, Talazoparib 380.3 reduction (CC< 60 ml/ No data NA [63,65–67] 14% with faeces min) Increased risk of Trastuzumab 145 kDa No data Not indicated NA [56–58], cardiotoxicity Mainly with Trastuzumab Increased risk of 148 k faeces Not indicated NA [59] emtansine cardiotoxicity (metabolites) Pertuzumab 148 k No data Not indicated No data NA [61] Atezolizumab 144 k No data Not indicated Safe (very limited data) NA [68–70] Abbreviations: CC, creatinine clearance; HD, haemodialysis; NA, not applicable. According to the summary of product characteristics, it (25% decrease of the daily dose) is recommended [64]. Talazoparib is eliminated in an unchanged form by the is not necessary to modify the dose of T-DM1 in patients with mild-to-moderate renal impairment [59]. kidneys [65]. Like in the case of olaparib, a 25% daily dose reduction of talazoparib is recommended in patients with moderate CKD (CC 30–60 ml/min) [66, 67]. For both PARP 5.3. Pertuzumab. )is drug is used in combination with inhibitors, there are no sufficient pharmacokinetic data in trastuzumab and DXL in patients with metastatic HER2- patients with severe CKD and ESKD. High rates of mye- positive breast cancer or unresectable local recurrence. It is lotoxicity, including severe anaemia, may be expected in also used in neo/adjuvant therapy in early breast cancer. CKD patients. Pertuzumab is a humanized monoclonal antibody with a high MM that prevents it from being removed through the HD membrane. Proteolytic degradation constitutes the main 7. Immune Therapy mechanism of the elimination of pertuzumab, as other Atezolizumab is a fully humanized, IgG1 isotype mono- antibodies, from the circulation. clonal antibody against the programmed cell death-ligand 1 According to the summary of product characteristics, it (PD-L1). It was recently approved by the EMA and the FDA is not necessary to modify the dose of pertuzumab in pa- for treatment of advanced triple-negative breast cancer (plus tients with mild or moderate renal impairment. Because of nab-paclitaxel) [68]. )e antibodies are slowly cleared from the limited number of pharmacokinetic data, there is no the circulation mainly by catabolism. )ere are no data on recommendation for administering the drug to patients with the safety of atezolizumab in CKD breast cancer patients. severe renal impairment including ESKD. Regardless of the )e only data came from the IMvigor210 study which in- coexistence of CKD, during the administration of pertu- volved 83 patients with locally advanced or metastatic zumab, the left ventricular ejection fraction should be urothelial carcinoma and decreased CC (30–60 mL/min) monitored due to the risk of congestive heart failure, which treated with atezolizumab without a dose reduction. )e is an infrequent complication of this therapy [61]. therapy was well tolerated [69]. Similarly, good tolerance of therapy was reported in a single HDpatient with metastatic 6. Poly ADP-Ribose Polymerase urothelial cell carcinoma [70]. )ese data show no need for a (PARP) Inhibitors dose adjustment in patients with mild-to-moderate CKD, and probably ESKD. Both olaparib (MM: 435 Da) and talazoparib (MM: 380 Da) are PARP inhibitors—an enzyme involved in DNA repair. )ey are both approved for the therapy of germline BRCA- 8. Summary mutated, HER2-negative metastatic breast cancer [62, 63]. )ese small molecules are strongly bound to proteins. It should be noted that for the older drugs, the safety in HD Olaparib is eliminated, mostly as metabolites, with the faeces patients is ensured in most cases (Table 1). )ere are in- and the urine in similar amounts. Due to the increased AUC sufficient data on treating HD patients with letrozole, (by 44%) and Cmax (by 26%) in patients with moderate paclitaxel, cyclophosphamide, and all newer medical renal impairment (CC 30–50 ml/min), a dose adjustment products: CDK4/6 inhibitors, neratinib, PARP inhibitors, Journal of Oncology 9 [8] Global Burden of Disease Cancer Collaboration, “Global, T-DM1, pertuzumab, and atezolizumab. 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Journal of Oncology – Hindawi Publishing Corporation
Published: May 18, 2020