Doxorubicin-based Chemotherapy Research Articles

Concurrent use of rabacfosadine and L-asparaginase for relapsed or refractory multicentric lymphoma in dogs.

BackgroundRabacfosadine (RAB), a novel antineoplastic agent conditionally licensed for the treatment of lymphoma in dogs, is efficacious in both naïve and previously treated dogs. Its use in combination with L‐asparaginase (L‐ASP) has not been studied.Hypothesis/ObjectivesTo evaluate the safety and efficacy of L‐ASP given concurrently with RAB in dogs with relapsed multicentric lymphoma.AnimalsFifty‐two dogs with relapse of lymphoma after treatment with at least 1 doxorubicin‐based chemotherapy protocol.MethodsOpen‐label, multicenter, prospective single‐arm clinical trial. Dogs were treated with RAB at 1.0 mg/kg IV every 21 days for up to a total of 5 doses. L‐asparaginase was administered at 400 IU/kg SQ concurrently with the first 2 treatments of RAB.ResultsThe overall response rate (ORR) for all dogs was 67%, with 19 dogs (41%) achieving a complete response (CR). The median progression‐free survival time (MPFS) was 63 days (range 5‐428 days). Dogs experiencing a CR as their best response had an MPFS of 144 days (range 44‐428 days). Adverse events were similar to previous studies evaluating single agent RAB. Failure to achieve a CR and having previously received L‐ASP were negative prognostic factors on multivariate analysis.Conclusions and Clinical ImportanceConcurrent RAB/L‐ASP appears to be both efficacious and safe for treating relapsed multicentric lymphoma in dogs. Adverse events were most often mild and no unexpected toxicoses were observed.

Time-dependent simvastatin administration enhances doxorubicin toxicity in neuroblastoma

Statins have a primary indication for the reduction and management of hypercholesterolemia; however, evidence shows that statins have the ability to increase the toxicity of chemotherapeutics within cancer cells by inducing anti-proliferative, anti-metastatic, and anti-angiogenic effects. More recently, lipophilic statins have shown complex interaction with energy metabolism, specifically acute mitochondrial dysfunction and delayed inhibition of glycolysis. With the goal to demonstrate that statin-mediated enhancement of chemotherapeutics is time-dependent, we hypothesized that the lipophilic statin simvastatin, in conjunction with variable co-exposure of doxorubicin or cisplatin, will enhance the toxicity of these drugs in neuroblastoma. Utilizing human SK-N-AS neuroblastoma cells, we assessed cell proliferation, necrosis, caspase activation, and overall apoptosis of these cells. After determining the toxicity of simvastatin at 48 h post-treatment, 10μM was chosen as the intervention concentration. We found that significant cell death resulted from 1.0μM dose of doxorubicin with 24 h pre-treatment of simvastatin. On the other hand, simvastatin enhancement of cisplatin toxicity was only observed in the co-exposure model. As doxorubicin has strict dosage limits due to its primary off-target toxicity in cardiac muscle, we further compared the effects of this drug combination on rat H9C2 cardiomyoblasts. We found that simvastatin did not enhance doxorubicin toxicity in this cell line. We conclude that simvastatin provides time-dependent sensitization of neuroblastoma cells to doxorubicin toxicity, and our results provide strong argument for the consideration of simvastatin as an adjuvant in doxorubicin-based chemotherapy programs.

Regulated Alternative Translocation: A Mechanism Regulating Transmembrane Proteins Through Topological Inversion.

Transmembrane proteins must adopt a proper topology to execute their functions. In mammalian cells, a transmembrane protein is believed to adopt a fixed topology. This assumption has been challenged by recent reports that ceramide or related sphingolipids regulate some transmembrane proteins by inverting their topology. Ceramide inverts the topology of certain newly synthesized polytopic transmembrane proteins by altering the direction through which their first transmembrane helices are translocated across membranes. Thus, this regulatory mechanism has been designated as Regulated Alternative Translocation (RAT). The physiological importance of this topological regulation has been demonstrated by the finding that ceramide-induced RAT of TM4SF20 (Transmembrane 4 L6 family member 20) is crucial for the effectiveness of doxorubicin-based chemotherapy, and that dihydroceramide-induced RAT of CCR5 (C-C chemokine receptor type 5), a G protein-coupled receptor, is required for lipopolysaccharide (LPS) to inhibit chemotaxis of macrophages. These observations suggest that topological inversion through RAT could be an emerging mechanism to regulate transmembrane proteins.

A phase II of gemcitabine combined with pazopanib followed by pazopanib maintenance, as second-line treatment in patients with advanced leiomyosarcomas: A unicancer French Sarcoma Group study (LMS03 study)

BackgroundOptions in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting. Patients and methodsPatients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%. Results106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1–41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6–8.2), and the overall survival was 22.4 months (95% CI 16.9–26.5). The best response was 23.8%. The most frequent reported grade 3–4 adverse events were haematological. ConclusionsLMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients.Eudract N°2011-001308-36 and NCT01442662.

CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer.

Cannabidiol (CBD) has emerged as a potential agent for breast cancer management. In this work, the potential use of cannabidiol in solution (CBDsol) and encapsulated in polymeric microparticles when combined with paclitaxel (PTX) and doxorubicin (DOX) in breast cancer treatment has been evaluated for the first time using MCF-7 and MDA-MB-231 cells. CBDsol, previously administered at suboptimal concentrations (cell death<10%), enhanced the PTX and DOX effect in both breast cancer cells. The co-administration of CBDsol and PTX or DOX showed a synergistic effect. PLGA-502 was selected as the most suitable polymer to develop CBD-loaded microparticles. The developed formulation (CBD-Mps) was effective as monotherapy, showing extended antiproliferative activity for at least 10days, and when combined with PTX or DOX. In fact, the use of CBD-Mps allows the combination of both, pre and co-administration strategies, with a single administration, also showing a significant increase in PTX and DOX antiproliferative activity. Finally, the anticancer effect of both CBDsol and CBD-Mps as monotherapy or in combination with PTX was also confirmed in ovo, usingMDA-MB-231-derived tumours. This data evidences the promising inclusion of CBD in conventional breast cancer chemotherapy and the use of CBD-Mps for the extended release of this cannabinoid, optimising the effect of the chemotherapeutic agents.

A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. IMPLICATIONS: These findings underlie the importance of a novel morphologic-metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

Impact of Arterial Hypertension on Doxorubicin-Based Chemotherapy-Induced Subclinical Cardiac Damage in Breast Cancer Patients.

Advances in oncologic therapies have allowed to achieve better outcomes and longer survival in many patients with breast cancer. Anthracyclines are cytotoxic antibiotics widely used in daily oncology practice. However, anthracyclines cause cardiotoxicity which is a limiting factor of its use. Cumulative dose of anthracyclines is the major cause of induced cardiotoxicity. According to previous clinical trials, the major predisposing high-risk factors for anthracycline-based chemotherapy-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as diabetes and hypertension. Experimental studies in animals confirm that hypertension may be a significant factor predisposing anthracycline-based chemotherapy cardiotoxicity. The main objective of our study was to identify the effect of pre-existing arterial hypertension on the development of subclinical cardiac damage during or after doxorubicin-based chemotherapy in breast cancer patients. The study was performed prospectively between March 2016 and January 2017 in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics Department of Oncology and Department of Cardiology. Data of 73 women with breast cancer treated with doxorubicin-based chemotherapy in outpatient clinic were analyzed. Statistically significant association between pre-existing arterial hypertension and left ventricular systolic dysfunction after completion of chemotherapy was observed (P < 0.004). Our study demonstrated that pre-existing arterial hypertension has a very important role in the development of anthracycline-based chemotherapy-induced cardiotoxicity, despite arterial hypertension control quality. Consequently, further studies evaluating impact of other risk factors and how early and sufficient management of arterial hypertension could influence the development of cardiotoxicity are needed to avoid permanent cardiac damage.

High drug efflux pump capacity and low DNA damage response induce doxorubicin resistance in canine hemangiosarcoma cell lines

Canine hemangiosarcoma (HSA) is an aggressive malignant endothelial tumor in dogs and characterized by poor prognosis because of its high invasiveness, high metastatic potential, and poor responsiveness to anti-cancer drugs. Although doxorubicin-based chemotherapy is regularly conducted after surgical treatment, its effects on survival rates are limited. Acquisition of drug resistance is one of the causes of this problem, but the underlying mechanisms remain unclear. In the present study, we aimed to identify the drug-resistance mechanism in canine HSA by establishing doxorubicin-resistant (DR) HSA cell lines. HSA cell lines were exposed to doxorubicin at gradually increasing concentrations. When the cells were able to grow in the presence of a 16-fold higher doxorubicin concentration compared with the initial culture, they were designated DR-HSA cell lines. Characterization of these DR-HSA cell lines revealed higher drug efflux pump capacity compared with the parental cell lines. Furthermore, the DR-HSA cell lines did not show activation of the DNA damage response despite carrying high DNA damage burdens, meaning that apoptosis was not strongly induced. In conclusion, canine HSA cell lines acquired doxorubicin resistance by increasing their drug efflux pump capacity and decreasing the DNA damage response. This study provides useful findings to promote further research on the drug-resistance mechanisms in canine HSA.

1731TiP - EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)

BackgroundIn advanced STS, median progression-free survival (PFS) remains at 4 months (mo) and median overall survival (OS) is about 12-18mo after Doxo-CT. There is currently no maintenance therapy available. A phase III trial has shown a modest benefit of a maintenance with ridafolimus compared to placebo (PBO) (PFS, 17.7 vs 14.6 weeks, HR=0.72). REG is an orally bioavailable multikinase inhibitor with meaningful activity in doxorubicin-refractory non-adipocytic STS. In a prior randomized phase II trial (REGOSARC; NCT01900743), median PFS was 4.0mo with REG compared to 1.0 with PBO (HR=0.36, p<0.0001) and median OS was 13.4 vs 9.0mo (HR=0.67; p=0.059). Trial designEREMISS (NCT03793361) is a multicenter (17 centers from the French Sarcoma Group) double-blind controlled randomized phase II trial assessing efficacy and safety of REG compared to PBO as maintenance therapy in metastatic / locally advanced STS experiencing stable disease (SD) or partial response (PR) after 6 cycles of Doxo-CT as 1st-line. The primary endpoint is PFS (RECIST 1.1, centrally reviewed). Secondary endpoints are efficacy (OS, Objective response, time to start subsequent therapy), safety and benefit/risk ratio (Q-TWIST). The randomization is balanced 1:1 and controlled for histology (leiomyosarcoma/synovial sarcoma/other sarcoma), response to CT (SD/PR) and centers. Pts receive either REG (120mg/d 21/28 days) or PBO until unacceptable toxicity, progression or consent withdrawal. There is no cross-over in this trial. Main eligibility criteria are: age ≥18; histologically-proven non-adipocytic STS, metastatic / locally advanced STS not amenable to curative intent surgery, PS<2, measurable disease, SD or PR after 6 cycles of Doxo-CT. Based on the following assumptions: PFS, 7 (REG) vs 4mo (PBO), HR=0.57, 1-sided α=5% and β=10%, the required number of events is 110 and the sample size is 126 pts. The planned study duration is 30 months. Enrolment is open since 12/2018. Clinical trial identificationNCT03793361. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA. Le Cesne: Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids.

Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer’s and Parkinson’s disease).

Adjuvant anthracycline‐based vs metronomic chemotherapy vs no medical treatment for dogs with metastatic splenic hemangiosarcoma: A multi‐institutional retrospective study of the Italian Society of Veterinary Oncology

Treatment options for dogs with metastatic (stage III) splenic hemangiosarcoma are limited. A doxorubicin-based chemotherapy regimen is commonly administered; however, there are no published data to support this practice. The aim of this study was to investigate the impact of maximum-tolerated-dose chemotherapy (MTD), metronomic chemotherapy (MC) and no adjuvant treatment on outcome in dogs with stage III splenic hemangiosarcoma undergoing splenectomy. Medical records of dogs with stage III splenic hemangiosarcoma that underwent splenectomy followed by MTD chemotherapy, MC or no adjuvant treatment were retrieved. Time to progression (TTP), survival time (ST) and toxicity were evaluated. One hundred three dogs were identified: 23 received adjuvant MTD, 38 MC and 42 were not medically treated. Overall median TTP and ST were 50 (95% confidence interval [CI], 39-61) and 55 days (95% CI, 43-66), respectively. Dogs treated with adjuvant MTD had a significantly longer TTP and ST compared with dogs receiving MC (median TTP, 134 vs 52 days, P = .025; median ST, 140 vs 58 days, P = .023, respectively). Dogs treated by splenectomy only had the shortest median TTP (28 days) and ST (40 days). However, treatment-related adverse events (AEs) were significantly more frequent in the MTD group (P = .017). The outcome for dogs with metastatic splenic hemangiosarcoma is poor. While MTD showed greater efficacy compared to MC, toxicity was higher in this group. Treatment-related AEs need to be carefully balanced against this modest survival prolongation when offering adjuvant MTD to dogs with advanced stage hemangiosarcoma.

The true colors of autophagy in doxorubicin-induced cardiotoxicity.

Patients with cancer receiving doxorubicin-based chemotherapy often have to stop taking the drug due to its cardiotoxicity and therefore lose out on the beneficial effects of its potent antitumor activity. Doxorubicin has been demonstrated to damage cardiomyocytes via various mechanisms, including accumulation of reactive oxygen species (ROS), DNA damage and autophagy dysfunction. The present review focuses on autophagy, describing the general process of autophagy and the controversy surrounding its role in doxorubicin-induced cardiotoxicity. In addition, the associations between autophagy and apoptosis, ROS, DNA damage and inflammatory processes are discussed. In the future, it will be useful to further elucidate the process of autophagy and reveal its association with various pathological processes to develop effective strategies of preventing doxorubicin-induced cardiotoxicity.

Olaratumab administered in two cases of phyllodes tumour of the breast: end of the beginning?

Phyllodes tumours of the breast are rare mesenchymal tumours with differential malignant potential. Treatment of choice is radical excision with negative margins. Radiation therapy has shown controversial results in small series. Chemotherapy in the adjuvant setting still remains a matter of debate. Doxorubicin-based chemotherapy is recommended for breast sarcomas’ first-line treatment. Herein we present two cases of breast phyllodes tumour treated with the recent combination of doxorubicin and olaratumab.

Desmoid-type Fibromatosis

Desmoid-type fibromatosis is a rare disease that does not have metastatic potential. It can be locally aggressive or regress spontaneously. For this reason, and because many of these tumors are inoperable or surgery is associated with significant morbidity, nonoperative treatment modalities are now more commonly employed to manage these lesions. Active observation, ablative therapies, and systemic treatments such as doxorubicin-based chemotherapy or sorafenib can be prescribed to minimize morbidities associated with the disease and surgical intervention. A thorough understanding regarding desmoid biology and the relative indications for multimodality therapies is essential to triage patients for appropriate interventions. This review contains 5 figures, and 29 references. Key Words: active observation, β-catenin, desmoid, familial adenomatous polyposis, fibromatosis, soft tissue tumors

Desmoid-type Fibromatosis

Desmoid-type fibromatosis is a rare disease that does not have metastatic potential. It can be locally aggressive or regress spontaneously. For this reason, and because many of these tumors are inoperable or surgery is associated with significant morbidity, nonoperative treatment modalities are now more commonly employed to manage these lesions. Active observation, ablative therapies, and systemic treatments such as doxorubicin-based chemotherapy or sorafenib can be prescribed to minimize morbidities associated with the disease and surgical intervention. A thorough understanding regarding desmoid biology and the relative indications for multimodality therapies is essential to triage patients for appropriate interventions. This review contains 5 figures, and 29 references. Key Words: active observation, β-catenin, desmoid, familial adenomatous polyposis, fibromatosis, soft tissue tumors

From the Literature

From the Literature

Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis

BackgroundGastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues.ResultsOral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity.ConclusionsAltogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.

Positive effects of acupressure bands combined with relaxation music/instructions on patients most at risk for chemotherapy-induced nausea

Research by our group has shown that acupressure bands are efficacious in reducing chemotherapy-induced nausea (CIN) for breast cancer patients who expect nausea, and that their effectiveness in controlling CIN can largely be accounted for by patients' expectations of efficacy, i.e., a placebo effect. The present research examined if the effectiveness of acupressure bands could be enhanced by boosting patients' expectation of the bands' efficacy. Two hundred forty-two chemotherapy-naïve patients with breast cancer who expected nausea were randomized. Arms 1 and 2 received acupressure bands, plus a relaxation MP3 and written handout that were either expectancy-enhancing (arm 1) or expectancy-neutral (arm 2). Arm 3 was the control without bands or MP3 and received standard care. All participants received guideline-specified antiemetics. Peak CIN for arms 1, 2, and 3 on a 1-7 scale was 3.52, 3.55, and 3.87, respectively (p = 0.46). Because no differences were observed between arms 1 and 2 (primary analysis), we combined these two arms (intervention) and compared them to controls for the following analyses. A significant interaction was found between intervention/control and receiving doxorubicin-based chemotherapy (yes/no) and pre-treatment anxiety (high/low). Intervention patients receiving doxorubicin had lower peak CIN than controls (3.62 vs. 4.38; p = 0.02). Similarly, intervention patients with high pre-treatment anxiety had a lower peak CIN than controls (3.62 vs. 4.62; p = 0.01). In breast cancer patients undergoing chemotherapy and having high CIN expectation, acupressure bands combined with a relaxation recording were effective in reducing CIN for patients who received doxorubicin or had high anxiety.

A meta-analysis of randomized controlled trials that compare standard doxorubicin with other first-line chemotherapies for advanced/metastatic soft tissue sarcomas.

ObjectiveThe standard treatment for patients with advanced/metastatic soft tissue sarcomas (ASTS) is systemic chemotherapy with doxorubicin. A previous meta-analysis of 8 randomized controlled trials (RCTs) demonstrated the superiority of single-agent doxorubicin over doxorubicin-based combination chemotherapy for ASTS. However, meta-analyses of all RCTs that compare doxorubicin to other single-agent or combination regimens as first-line treatments for ASTS are lacking. We conducted a systematic review and meta-analysis to evaluate the efficacy and toxicity of current primary treatments for ASTS.MethodsEligible studies were RCTs of first-line chemotherapies for ASTS comparing doxorubicin alone to other single agents or to combination therapies (experimental arm). Data from studies reporting hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) were pooled. Other time-to-event endpoints were extracted from the studies based on Kaplan-Meier estimates, and pooled odds ratios (OR) and 95% CI were calculated.ResultsTwenty-seven eligible RCTs comprising 6156 patients were identified. Overall, the 1-year OS (OR 0.88, 95% CI 0.79–0.99, P = 0.03) was significantly improved in the experimental arm over the doxorubicin-only arm; however, there was no significant difference in 2-year OS (OR 0.87, 95% CI 0.73–1.03, P = 0.11) or OS (HR 0.97, 95% CI 0.91–1.03, P = 0.28) between the two groups. PFS and other time-to-event endpoints were not significantly different between the two treatment arms. While incidences of overall severe adverse events were not significantly different (OR 1.20, 95% CI 0.88–1.65, P = 0.26), severe nausea/vomiting was significantly more frequent in the experimental arm (OR 1.90, 95% CI 1.27–2.83, P = 0.002).ConclusionThe efficacies of doxorubicin-only and experimental arm regimens were similar, although toxicities were more frequent in the experimental arms. Hence, doxorubicin monotherapy remains suitable as a standard first-line regimen for ASTS.

Comparison of the MAID (AI) and CAV/IE regimens with the predictive value of cyclic AMP-responsive element-binding protein 3 like protein 1 (CREB3L1) in palliative chemotherapy for advanced soft-tissue sarcoma patients.

Background: Palliative chemotherapy is currently the first-line treatment for advanced soft tissue sarcoma. The purpose of this study was to compare the efficacies of the MAID (AI) and CAV/IE alternating regimens in advanced soft-tissue sarcoma patients. Since resistances to ADM-based chemotherapy and toxicity from doxorubicin are frequently observed in clinical practice, we investigated the association between CREB3L1 expression and survival in advanced soft-tissue sarcomas patients treated with doxorubicin-based palliative chemotherapy.Methods: The cohort under investigation comprised 152 patients who underwent doxorubicin-based first-line palliative chemotherapy for advanced soft-tissue sarcoma at our institution between January 2010 and April 2017. Immunohistochemical analysis and the reverse transcription polymerase chain reaction were used to determine the expression of CREB3L1 in soft-tissue sarcoma specimens prior to first-line palliative chemotherapy. Univariate and multivariate analyses were performed on chemotherapy regimens and CREB3L1 expression levels. The relationship between CREB3L1 expression and survival was also analyzed.Results: The CAV/IE alternating regimen yielded favorable outcomes for response and survival in patients compared with those who received MAID (AI) treatment. The most common toxicity of grades 3 and 4 was leukopenia (58.5 % in the MAID (AI) regimen; 37.1 % in the CAV/IE regimen). The incidence of febrile neutropenia after CAV/IE treatment (7.1 %) was lower than after MAID (AI) treatment (13.4 %). Grade 3 neuralgia was observed in 1.2 % of patients receiving the MAID regimen versus 8.6 % in patients receiving the CAV/IE regimen. High CREB3L1 expression was observed in 48 of 152 patients (31.6 %). Overall survival was significantly higher for CREB3L1 high-expression patients than for CREB3L1 low-expression patients, especially for those also treated with the MAID (AI) regimen. The CREB3L1 expression level was identified as an independent prognostic factor for survival by multivariate analysis.Conclusions: Our study suggests that the CAV/IE alternating regimen may be associated with a better response and more favorable survival than the MAID (AI) regimen in advanced soft-tissue sarcoma patients. Furthermore, the CREB3L1 expression level may predict the efficacy and survival of doxorubicin-based palliative chemotherapy for advanced soft-tissue sarcoma.