PMC:4822111 / 12949-28984 JSONTXT

{"project":"2_test","denotations":[{"id":"27066091-21376385-56335797","span":{"begin":448,"end":450},"obj":"21376385"},{"id":"27066091-25605862-56335798","span":{"begin":448,"end":452},"obj":"25605862"},{"id":"27066091-21376385-56335799","span":{"begin":1165,"end":1167},"obj":"21376385"},{"id":"27066091-25605862-56335800","span":{"begin":1165,"end":1169},"obj":"25605862"},{"id":"27066091-21376385-56335801","span":{"begin":1778,"end":1780},"obj":"21376385"},{"id":"27066091-25605862-56335802","span":{"begin":1778,"end":1782},"obj":"25605862"},{"id":"27066091-21376385-56335803","span":{"begin":1924,"end":1926},"obj":"21376385"},{"id":"27066091-25605862-56335804","span":{"begin":1924,"end":1928},"obj":"25605862"},{"id":"27066091-21376385-56335805","span":{"begin":2041,"end":2043},"obj":"21376385"},{"id":"27066091-25605862-56335806","span":{"begin":2041,"end":2045},"obj":"25605862"},{"id":"27066091-21989327-56335807","span":{"begin":2511,"end":2513},"obj":"21989327"},{"id":"27066091-15967836-56335808","span":{"begin":2954,"end":2956},"obj":"15967836"},{"id":"27066091-21095116-56335809","span":{"begin":4313,"end":4315},"obj":"21095116"},{"id":"27066091-20555091-56335810","span":{"begin":4339,"end":4341},"obj":"20555091"},{"id":"27066091-20555091-56335811","span":{"begin":5508,"end":5510},"obj":"20555091"},{"id":"27066091-21989327-56335812","span":{"begin":5880,"end":5882},"obj":"21989327"},{"id":"27066091-16575015-56335813","span":{"begin":7668,"end":7670},"obj":"16575015"},{"id":"27066091-21569993-56335814","span":{"begin":7731,"end":7733},"obj":"21569993"},{"id":"27066091-21376385-56335815","span":{"begin":7975,"end":7977},"obj":"21376385"},{"id":"27066091-21376385-56335816","span":{"begin":8204,"end":8206},"obj":"21376385"},{"id":"27066091-21376385-56335817","span":{"begin":8716,"end":8718},"obj":"21376385"},{"id":"27066091-22282463-56335818","span":{"begin":9040,"end":9042},"obj":"22282463"},{"id":"27066091-22282463-56335819","span":{"begin":9139,"end":9141},"obj":"22282463"},{"id":"27066091-21989327-56335820","span":{"begin":9481,"end":9483},"obj":"21989327"},{"id":"27066091-15102312-56335821","span":{"begin":10325,"end":10327},"obj":"15102312"},{"id":"27066091-15759068-56335822","span":{"begin":10325,"end":10329},"obj":"15759068"},{"id":"27066091-16473643-56335823","span":{"begin":10325,"end":10331},"obj":"16473643"},{"id":"27066091-17693343-56335824","span":{"begin":10325,"end":10333},"obj":"17693343"},{"id":"27066091-18281158-56335825","span":{"begin":10325,"end":10335},"obj":"18281158"},{"id":"27066091-18281158-56335826","span":{"begin":10603,"end":10605},"obj":"18281158"},{"id":"27066091-12901290-56335827","span":{"begin":10603,"end":10607},"obj":"12901290"},{"id":"27066091-15346996-56335828","span":{"begin":10603,"end":10609},"obj":"15346996"},{"id":"27066091-15637653-56335829","span":{"begin":10603,"end":10611},"obj":"15637653"},{"id":"27066091-17992096-56335830","span":{"begin":10603,"end":10613},"obj":"17992096"},{"id":"27066091-19139108-56335831","span":{"begin":10603,"end":10615},"obj":"19139108"},{"id":"27066091-19417586-56335832","span":{"begin":10603,"end":10617},"obj":"19417586"},{"id":"27066091-22910842-56335833","span":{"begin":10734,"end":10736},"obj":"22910842"},{"id":"27066091-19755042-56335834","span":{"begin":10734,"end":10738},"obj":"19755042"},{"id":"27066091-24733808-56335835","span":{"begin":11607,"end":11609},"obj":"24733808"},{"id":"27066091-21376385-56335836","span":{"begin":11782,"end":11784},"obj":"21376385"},{"id":"27066091-25605862-56335837","span":{"begin":11782,"end":11786},"obj":"25605862"},{"id":"27066091-19341937-56335838","span":{"begin":11880,"end":11882},"obj":"19341937"},{"id":"27066091-21376385-56335839","span":{"begin":13077,"end":13079},"obj":"21376385"},{"id":"27066091-25605862-56335840","span":{"begin":13231,"end":13233},"obj":"25605862"},{"id":"27066091-20555089-56335841","span":{"begin":13815,"end":13817},"obj":"20555089"},{"id":"27066091-21947834-56335842","span":{"begin":13815,"end":13819},"obj":"21947834"},{"id":"27066091-23010853-56335843","span":{"begin":14021,"end":14025},"obj":"23010853"},{"id":"27066091-23010853-56335844","span":{"begin":14391,"end":14393},"obj":"23010853"}],"text":"MANAGEMENT OF ADVERSE EVENTS ASSOCIATED WITH ERIBULIN\nThe reported AEs in the EMBRACE study and Study 301 were consistent with the known side effect profile of eribulin from the previous phase II studies. The overall incidences of serious AEs in the two phase III trials are shown in Table 4. The main AEs leading to treatment discontinuation in the EMBRACE study and Study 301 were peripheral neuropathy (5%) and neutropenia (1.7%), respectively [2122]. The most common nonhematologic AEs of eribulin were asthenia/fatigue, alopecia, and nausea, while the most common hematologic AEs were neutropenia and leukopenia (Table 4).\nDelays in administration and/or dose reduction are sometimes needed to manage eribulin-related grade 3/4 toxicities. These dose reductions allow most patients to continue with the treatment longer in order to gain the maximal clinical benefit. Dose modification recommendations for eribulin retreatment are shown in Table 5 [15].\n\nNeutropenia and febrile neutropenia\nThe most commonly reported AEs associated with eribulin treatment in clinical trials are hematological effects attributed to bone marrow suppression (i.e., neutropenia) [2122]. This is consistent with our clinical experience of treating Asian patients with eribulin. In the EMBRACE study and Study 301, there was no prophylactic use of growth factors to prevent eribulin-induced neutropenia. Patients who developed neutropenia during eribulin treatment were managed with treatment delays, dose reductions, and granulocyte colony-stimulating factor (G-CSF), which was used in 18% and 14.6% of patients in the EMBRACE study and Study 301, respectively. Only 0.6% and 1.7% of patients discontinued eribulin treatment due to neutropenia in the EMBRACE study and Study 301, respectively [2122]. The median time to recovery from grade 3/4 neutropenia to grade 2 or lower was 8 days, but in some cases, this was extended up to 51 days [2122]. In the EMBRACE study and Study 301, febrile neutropenia (FN) occurred in 5% and 2% of patients, respectively [2122].\nIn the Asian population, based on the phase II trial of eribulin in Japanese patients, neutropenia was reported at a relatively higher incidence of 98.8% (all grades; 95.1% for grade 3/4) than in the Western population in the phase III trials. There was also a higher incidence of FN (13.6%), and G-CSF was administered to 25.9% of the patients to manage symptomatic neutropenia. However, only one patient (1%) discontinued eribulin treatment due to neutropenia [20].\nNeutropenia and FN are the major dose-limiting toxicities of some of the systemic cancer chemotherapies, including eribulin and other myelosuppressive chemotherapeutic agents such as paclitaxel, docetaxel, vinorelbine, and anthracyclinecontaining regimens. Advanced age, poor performance status, comorbidities, and low baseline blood cell counts have been identified as significant predictors for neutropenic complications, including FN [35]. However, eribulin-associated neutropenia is reversible and not cumulative; in most cases, it can be managed with dose delays or modification alone, or with the use of growth factors [15]. Eribulin should not be initiated in patients with an absolute neutrophil count (ANC) \u003c1,000/mm3, or with other hematologic toxicity at grade 2 or higher. If neutropenia occurs, a dose delay of 3 to 7 days should be considered in order to allow the ANC to recover, followed by a reduced dose schedule as specified in the dosing recommendations for eribulin (Table 5). Eribulin is associated with a low risk of FN, and primary prophylaxis with growth factors was not permitted in the aforementioned phase III trials of eribulin. However, maintaining adequate dose intensity is recognized as a key factor influencing a tumor's response to cytotoxic drugs. Therefore, primary or secondary prophylactic use of G-CSF may be considered, if needed, to maximize treatment benefit.\nThe prophylactic use of growth factors can reduce the risk, severity and duration of both severe and FN. The use of G-CSF or equivalent to manage eribulin-induced severe neutropenia is at the discretion of the treating physician, and in accordance with the relevant clinical practice guidelines, such as the guidelines of the European Organisation for Research and Treatment of Cancer (EORTC) [36], NCCN [37], and ESMO [38]. In general, these guidelines recommend that FN risk factors, including disease, dose density, age, neutrophil count, and treatment intent, should be evaluated before administering each cycle of chemotherapy. These guidelines also recommend not to consider growth factor use for primary prophylaxis in patients with a low risk of FN (\u003c10%), unless they are at a significant risk of serious medical consequences of FN, or if a chemotherapy dose reduction would be detrimental to the clinical outcome [37]. The NCCN recommendation for growth factor use in the prophylaxis and treatment of FN, and the maintenance of scheduled dose delivery, is the administration of 5 µg/kg daily of filgrastim until post-nadir ANC recovery to normal or near normal levels. It is initiated on the next day, after more than 24 hours up to 3 to 4 days after the completion of chemotherapy and throughout post-nadir recovery [37]. The ESMO guidelines suggest using 5 µg/kg daily of G-CSF, administered subcutaneously 24 to 72 hours after the last day of chemotherapy, until sufficient or stable post-nadir ANC recovery is achieved (achieving a target ANC of \u003e10×109/L is not necessary) [38]. Pegfilgrastim is generally not recommended by the NCCN guidelines for use with weekly chemotherapeutic regimens (such as eribulin) owing to insufficient supporting data, although, it may be administered if chemotherapy is given every 2 weeks or more [37].\nA higher incidence of eribulin-associated neutropenia was reported by a clinical trial with Japanese patients [20], as well as from individual clinicians treating Asian patients in their daily practice who received eribulin; although, there is no published report, to our knowledge, so far. Currently there is evidence that the pharmacogenomics of eribulin in Asian breast cancer patients differ from that in the Western population. Another potential reason for the higher neutropenia rate in Asian patients may be related to the use of eribulin as a very late-line therapy in heavily pretreated patients; using G-CSF may help to reduce the neutropenia rate in such patients.\nIn our clinical practice, although the routine use of growth factors with eribulin therapy is not always necessary in Asian patients, G-CSF may be considered as primary or secondary prophylaxis for \"high-risk\" patients. For example, primary prophylaxis with G-CSF might be considered for patients who experienced significant hematologic toxicities or FN during previous chemotherapeutic regimens, or for patients at risk of infective complications without good access to care. In some countries, primary prophylaxis with G-CSF is not reimbursed by their national healthcare systems. Under these circumstances, a reduced initial dose of eribulin can be considered for patients at high risk of neutropenia. This reduced dose may then be increased to the full dose if eribulin is well tolerated during the first treatment cycle. Although this may compromise dose intensity, treatment decisions should be individualized in accordance with these limitations in the clinical setting.\n\nPeripheral neuropathy\nMicrotubule-targeted therapies, including taxanes, epothilones, and vinca alkaloids, are commonly associated with some forms of neuropathy; severe peripheral neuropathy (grade 3 or 4) has been reported in 30% of patients [39]. Eribulin is one such agent associated with neurotoxicity [40].\nPeripheral neuropathy was reported as one of the most common grade 3/4 AEs of eribulin in the phase III trials; it occurred in about 7% to 8% of patients. However, it only resulted in treatment discontinuation in less than 5% of patients [21]. The incidence of all grades of peripheral neuropathy in the eribulin group in the EMBRACE study was 35% (8% of grade 3 or higher), compared with the 45% (17/38, 5% of grade 3 or higher) observed in the taxanes-TPC subgroup [21]. In the pooled safety analysis from the two phase III studies and two phase II studies of patients with mBC, 7.7% of patients (116/1,503) treated with eribulin had grade 3 or higher peripheral neuropathy [41]. In patients with grade 3 or higher peripheral neuropathy who remained on eribulin, the symptoms improved to grade 2 or less after treatment delays and dose reductions. Most patients who had peripheral neuropathy at baseline did not experience a worsening of its severity during eribulin treatment [21]. Of these patients, most showed an improvement in the severity of peripheral neuropathy, and 50% of them experienced its resolution. The median time to improvement was 2.1 weeks, whereas the median time to resolution was 7.7 weeks [41]. Moreover, neuropathy lasting more than 1 year occurred in only 5% of the patients [42]. Peripheral neuropathy associated with eribulin was reversible in many, but not all, patients [42]. Collectively, the data suggest that the risk–benefit ratio for eribulin in relation to peripheral neuropathy supports the use of this drug for treating patients with breast cancer [41]. A lower incidence of peripheral sensory neuropathy (23.5% of all grades, 3.7% of grade 3, and no grade 4) was reported in the Japanese phase II trial [20]. This is consistent with our experience of treating Asian patients with eribulin, and demonstrates that neuropathy does not seem to be a major dose-limiting toxicity.\nChemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related serious AE that interferes with the efficacy of treatment and decreases patients' quality of life. Several classes of chemotherapeutic agents cause peripheral neuropathy, including platinum-based agents (cisplatin, carboplatin, and oxaliplatin), vinca alkaloids (vincristine and vinblastine), and taxanes (paclitaxel and docetaxel). The incidence and severity of neuropathy vary considerably for different agents when administered alone or in combination. The incidence of neuropathy was reported to be as high as 70% to 90% with vincristine, cisplatin, oxaliplatin, and paclitaxel treatment [4344454647]. The risk of developing both short- and long-term CIPN is highly dependent on factors such as the age, single-dose intensity, cumulative dose, duration of therapy, combination of neurotoxic agents, coexisting neuropathies, genetic susceptibility, and alcohol abuse [47484950515253]. This neuropathy predominantly consists of sensory symptoms, rather than motor symptoms, and it is dose dependent [5455]. The symptoms become progressively worse with chemotherapy continuation. The standards of care for patients at risk of, or experiencing, neuropathy are based on a thorough assessment of their sensory symptoms; dose adjustments for chemotherapy can be made based on these findings. There are no established agents recommended for the prevention of CIPN in cancer patients undergoing treatment with neurotoxic agents. When grade 3 or higher peripheral neuropathy occurs, eribulin should be delayed until recovery to grade 2 or less; eribulin should be discontinued if peripheral neuropathy higher than grade 3 reoccurs (Table 5). The symptomatic management of peripheral neuropathy should be based on physicians' assessments and clinical judgments. Available clinical guidelines, such as the ASCO clinical practice guidelines for CIPN, may serve as a useful reference [56].\n\nAlopecia\nAlopecia is another common AE associated with eribulin therapy. In the EMBRACE study and Study 301, 45% and 35% of patients experienced alopecia, respectively [2122]. Chemotherapy-induced hair loss is common, with an estimated overall incidence rate of 65% [57]. The frequency and severity of hair loss are variable, and are related to the specific chemotherapeutic agent and the treatment protocol. Eribulin-induced hair loss cannot be reliably predicted or prevented. The treating physician should discuss the treatment plan with the patient and their family in order to establish their expectations regarding eribulin treatment, in addition to communicating the risks of potential AEs such as alopecia. From the patient's perspective, the clinical benefit of eribulin should be balanced with its potential toxicities. Treatment choice should be based on the patient's personal preference and physician's best clinical judgment. To date, no approved pharmacological option exists for the prevention of chemotherapy-induced hair loss. Scalp cooling with a cold cap in order to reduce alopecia is available in some cancer centers; however, there is limited experience in applying this method to patients with eribulin-induced alopecia.\n\nNausea and vomiting\nNausea and vomiting are among the most common gastrointestinal AEs associated with eribulin therapy. In the EMBRACE study, 35% and 18% of the patients experienced nausea and vomiting, respectively [21]. However, these AEs were usually mild, with grade 3 and 4 toxicities occurring in \u003c1% of patients. A low incidence of both AEs was seen in Study 301 [22]. Although the emetogenic potential of eribulin is common, it is considered low in comparison to that of the other antineoplastic agents such as cisplatin, doxorubicin, and cyclophosphamide [58]. Based on our clinical experience, eribulin-induced nausea and vomiting are relatively uncommon and anti-emetic prophylaxis is usually not necessary for Asian patients. If these AEs do occur, treatment guidelines for managing chemotherapy-induced nausea and vomiting can be followed, such as the guidelines of the Multinational Association of Supportive Care in Cancer, ASCO, and NCCN [5960].\n\nEribulin in patients with hepatic or renal impairment\nPharmacokinetic studies of eribulin show that drug exposure is greater in patients with hepatic impairment or severely impaired renal function [1561]. Therefore, eribulin dose adjustments may be required for mBC patients with hepatic and renal impairment. Eribulin should be used with caution and at the discretion of the treating physician in such patients. The recommended doses of eribulin in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment are 1.1 and 0.7 mg/m2, respectively [61]. Eribulin has not been studied in patients with severe hepatic impairment (Child-Pugh C), but it is expected that a more significant dose reduction ma y be needed if eribulin is used in these patients. Patients with impaired renal function may also require a dose reduction although the optimal dose for this patient group remains to be established.\n\nEribulin in elderly patients\nNo dose adjustment is recommended for the elderly patient population [15]. The EMBRACE study did not include sufficient numbers of patients aged ≥65 years in order to determine whether these patients had a different treatment response than the younger patients. Similar incidences of AEs were observed between these two groups of patients in the EMBRACE study. In Study 301, it was reported that in the patients receiving eribulin, there was a slight increase in study withdrawal among older patients (\u003e65 years, 10.7%) compared to that observed for younger patients (≤65 years, 7.4%) [62]. There was also an increased trend in the incidence of grade 3/4 leukopenia in older patients (22.6%) when compared with younger patients (13.7%); similar results were observed for the incidence of grade 3/4 neutropenia (50.0% vs. 45.0%, respectively). In contrast, a decrease in the incidence of peripheral sensory neuropathy was observed in the older population. However, a similar OS benefit of eribulin was shown in the younger (≤65 years) and older (\u003e65 years) age groups in this cohort of patients [62]. For older patients (\u003e65 years), we recommend careful evaluation of the patients' conditions, including their bone marrow function, prior to eribulin treatment.\n"}