Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review
Frontiers in oncology. 2021;11:727010
More than 40 tyrosine kinase inhibitors (TKIs) have received hematological or oncological indications over the past 20 years, following the approval of imatinib, and many others are currently being tested in clinical and preclinical level. Beyond their common toxicities, no certain agent from this large class of molecularly targeted therapies was strongly associated with "off-target" impairment of neuromuscular transmission, and although myasthenia gravis (MG) is a well-characterized autoimmune disorder, only few sporadic events proven by serologically detected causative autoantibodies and/or by positive electrophysiological tests are reported in the literature. Herein, we present the first case of anti-MUSK (+) MG in a woman with metastatic BRAF-mutant melanoma after long-term treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by this report, a systematic literature review was conducted, summarizing all other cancer cases that developed MG, after exposure to any type of targeted agent and regardless of the underlying malignancy. All available data on the clinical diagnosis, the potential of administered TKIs to induce a seropositive myasthenic syndrome, the immune and non-immune-mediated pathogenesis of postsynaptic damage, and the challenging management of this neuromuscular toxicity were collected and discussed. In the presented case, MG was confirmed by both autoantibodies and nerve-conduction tests, while its reactivation after TKIs rechallenge supports a more than coincidental association. The following review identified 12 cancer cases with TKI-related MG in six case reports and one case series. In most of them, the myasthenia diagnosis was challenging, since the clinical symptomatology of fatigable weakness was not corroborating with consistent laboratory and electrophysiological findings. In fact, anti-AchR titers were positive in five and anti-MuSK only in the abovementioned individual. The symptomatology corresponded to TKI discontinuation and standard treatment with pyridostigmine and prednisolone; intravenous immunoglobulin was added only in three, and two required mechanical ventilation. In an era where TKIs will be prescribed more frequently for various malignancies, even in combinations with immune-checkpoint inhibitors, this report synthesizes their risk for neuromuscular complications and increases the clinicians' awareness in order to extend the on-treatment and overall survival of TKI-treated cancer patients.
Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis
Journal of Cancer. 2021;12(17):5164-5172
Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages. Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes. Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P<0.05). Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups (RR of ORR in metastatic vs early or locally advanced patients: 1.46 [1.09-1.96] vs 1.01 [0.94-1.08]; conventional vs dose dense group: 1.59 [1.23-2.06] vs 1.01 [0.91-1.12]). Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients.
Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review
Frontiers in medicine. 2021;8:759914
Background: Thymoma-associated haematological diseases (HDs), such as pure red cell aplasia (PRCA) and Good's syndrome, are extremely rare, and due to the paucity of large-scale studies, the characteristics, remission after thymectomy, and long-term evaluation remain undetermined. Methods: We retrospectively assessed patients with thymoma and associated HDs from Jan 2005 to Dec 2020. All patients received thymectomy and/or additional treatments for HDs. A comparison with thymoma-associated myasthenic gravis (MG), and a systematic review from PubMed/MEDLINE and Embase were conducted. Results: In the median follow-up of 56 months, 130 patients were enrolled. Patients with thymoma-associated MG (n = 46) and HDs [n = 8; PRCA (n = 5), PRCA and Good's syndrome (n = 2) and autoimmune haemolytic anaemia (n = 1)] were evaluated. Patients with MG had a significantly higher remission rate after thymectomy (50 vs. 17%; p = 0.0378) as compared to those with other autoimmune diseases. Two of seven patients with PRCA experienced remission with thymectomy alone, and an additional two patients achieved remission with thymectomy plus immunosuppressive therapy (IST). In the systematic review, 60 studies (case reports, n = 46; case series including the present study, n = 14) were evaluated. Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected. Conclusions: Our study indicates that patients with thymoma-associated autoimmune diseases other than MG have a lower remission rate than those with MG. Remission of thymoma-associated PRCA can be achieved by thymectomy and IST. This study provides insight into extremely rare but puzzling autoimmune manifestations.
Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non-Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial
Clinical lung cancer. 2020
BACKGROUND We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non-small-cell lung cancer. PATIENTS AND METHODS Patients with treatment-naive squamous non-small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m(2) on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m(2) (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). RESULTS Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator's discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). CONCLUSIONS The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.
Effects of Fibrin Sealant on Seroma Reduction for Patients with Breast Cancer Undergoing Axillary Dissection: Meta-Analysis of Randomized Controlled Trials
Ann Surg Oncol. 2020
BACKGROUND Seroma formation is common in patients with breast cancer after axillary dissection. Fibrin sealant, containing fibrinogen and thrombin, has been developed to improve wound healing. We conducted a systematic review and meta-analysis to evaluate the efficacy of fibrin sealants in reducing seroma among patients with breast cancer undergoing axillary dissection. METHODS We searched the PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials (RCTs) published up to April 2020. Pooled estimates of the outcomes were computed using a random-effects model. The primary outcomes were incidence and volume of seroma, while the secondary outcomes were volume and duration of drainage, incidence of infection, and length of hospital stay. RESULTS We reviewed 23 RCTs that included 1640 patients. Compared with the control group, the fibrin sealant group had no significant differences in the incidence of seroma, length of hospital stay, or incidence of surgical site infection. Significant intergroup differences were discovered in lower volume of seroma (weighted mean difference [WMD] - 71.88, 95% confidence interval [CI] - 135.58 to - 8.19), volume of drainage (WMD - 73.24, 95% CI - 107.32 to - 39.15), and duration of drainage (WMD - 0.84, 95% CI - 1.50 to - 0.19). CONCLUSIONS Fibrin sealants provide limited benefits in reducing the volume of seroma and the volume and duration of drainage. Therefore, after shared decision making, surgeons may apply fibrin sealants to patients with breast cancer undergoing axillary dissection.
Tissue sealants for the prevention of lymphoceles after radical inguinal lymph node dissection in patients with melanoma: A systematic review and individual patient data meta-analysis
Journal of surgical oncology. 2019
BACKGROUND AND OBJECTIVES Postoperative lymphoceles and further wound complications occur frequently after radical inguinal lymph node dissection (ILND). In various studies, tissue sealants have shown to reduce the incidence of postoperative morbidity. METHODS A systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effectiveness of tissue sealants in reducing the incidence of postoperative lymphoceles following ILND in patients with melanoma was conducted. Individual patient data was requested to pool the data for meta-analysis appropriately. RESULTS Thousand seven hundred twenty-nine manuscripts were screened for eligibility. Six RCTs published between 1986 and 2012 were identified including 194 patients for ILND. Only four RCTs were included in the meta-analysis. No study properly defined the term "lymphocele." Tissue sealants failed to influence the duration of drain placement (mean difference [MD] = -3.05 days; z = 1.18; P = 0.24), total drainage volume (MD = 598.39 mL; z = 1.49; P = 0.14), the incidence of postoperative seroma, wound infection and skin necrosis. CONCLUSIONS No improvement was identified with the use of tissue sealants, however, a valid comparison of the results of included trials was difficult owing to the lack of a definition of the term "lymphocele." Other surgical techniques and trials using validated endpoint definitions are required to reevaluate these findings.
Prognostic value of pretreatment albumin to bilirubin ratio in patients with hepatocellular cancer: A meta-analysis
BACKGROUND Hepatic function is closely associated with prognosis in patients with hepatocellular cancer (HCC). In this study, a meta-analysis of the published studies was performed to assess the prognostic value of ALBI grade in HCC patients. METHODS Databases, including PubMed, EMbase, Web of Science, and Cochrane Library were retrieved up to August 2018. The primary outcome was OS and secondary outcome was DFS, the prognostic impact of which was assessed by using hazard ratio (HRs) with corresponding 95% confidence intervals (CIs). The enrolled studies were analyzed by using STATA version 12.0 software. RESULTS A total of 22,911 patients with HCC in 32 studies were included. Our results demonstrated that high pretreatment ALBI is associated with poor OS (HR = 1.719, 95%CI: 1.666-1.771, P = .000, univariate results; HR = 1.602, 95%CI: 1.470-1.735, P = .000, multivariate results) and poor DFS (HR = 1.411, 95%CI: 1.262-1.561, P = .000, univariate results; HR = 1.264, 95%CI: 1.042-1.485, P = .000, multivariate results). Meanwhile, when the analysis was stratified into subgroups, such as treatment methods, sample size, geographic area, and ALBI grade, the significant correlation in ALBI and poor long-term survival was not altered. CONCLUSION High pretreatment ALBI is closely associated with poor prognosis in HCC, and High ALBI should be treated as an ideal predictor during hepatocellular therapy.
Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial
The Lancet Child & Adolescent Health. 2018;2((1)):25-34.
Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Patient and Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.
Subcutaneous immunoglobulin therapy for hypogammaglobulinemia secondary to malignancy or related drug therapy
Transfusion Medicine Reviews. 2016;31((1):):45-50
Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the health-related quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg.
Prospective randomized controlled study to assess the value of a hemostatic and sealing agent for preventing seroma after axillary lymphadenectomy
Journal of Surgical Oncology. 2016;114((4):):423-7
BACKGROUND AND OBJECTIVES Postoperative seroma after axillary lymphadenectomy leads to an increased use of resources and an impaired quality of life of patients. This randomized clinical trial was designed to assess the value of a hemostatic and sealing agent for decreasing seroma occurrence after axillary lymphadenectomy. METHODS A prospective, randomized, blind study was conducted on 91 axillary lymphadenectomies distributed into a control group (n = 47) and a test group in which a collagen sponge coated with human coagulation factors was used (n = 44). Primary end-points were number of days before removal of axillary drainage, axillary drainage output, and occurrence of seroma, wound infection, haematoma, or wound dehiscence, within 8 weeks of surgery. Bivariate and multivariate analyses on seroma occurrence were performed. RESULTS Seroma occurred in 29 patients (31.86%). A significant direct relationship (P = 0.002) was only noted between use of the hemostatic and sealing agent and nonoccurrence of seroma. In the multivariate study, the only variable found to be significantly related to seroma occurrence was use of the above agent (P = 0.046; odds ratio: 3.365 [95%CI: 1.024-11.060]). CONCLUSIONS Use of a collagen sponge coated with human coagulation factors following axillary lymphadenectomy was associated to a lower incidence of postoperative seroma. J. Surg. Oncol. (c) 2016 Wiley Periodicals, Inc.