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Journal of Clinical Oncology : Official... Jun 2023About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).
PURPOSE
About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking.
METHODS
In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively ( < .0001). The median PFS was 7.4 months versus 3.3 months ( < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months ( < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group.
CONCLUSION
IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.
Topics: Humans; Melphalan; Scandium; Prospective Studies; Chemotherapy, Cancer, Regional Perfusion; Liver Neoplasms; Perfusion
PubMed: 36940407
DOI: 10.1200/JCO.22.01705 -
Methods in Molecular Biology (Clifton,... 2019Drug resistance remains a critical problem for the treatment of multiple myeloma (MM), which can serve as a specific example for a highly prevalent unmet medical need...
Drug resistance remains a critical problem for the treatment of multiple myeloma (MM), which can serve as a specific example for a highly prevalent unmet medical need across almost all cancer types. In MM, the therapeutic arsenal has expanded and diversified, yet we still lack in-depth molecular understanding of drug mechanisms of action and cellular pathways to therapeutic escape. For those reasons, preclinical models of drug resistance are developed and characterized using different approaches to gain insights into tumor biology and elucidate mechanisms of drug resistance. For MM, numerous drugs are used for treatment, including conventional chemotherapies (e.g., melphalan or L-phenylalanine nitrogen mustard), proteasome inhibitors (e.g., Bortezomib), and immunomodulators (e.g., Lenalidomide). These agents have diverse effects on the myeloma cells, and several mechanisms of drug resistance have been previously described. The disparity of these mechanisms and the complexity of these biological processes lead to the formation of complicated hypotheses that require omics approaches for efficient and effective analysis of model systems that can then be interpreted for patient benefit. Here, we describe the combination of metabolomics and proteomics to assess melphalan resistance in MM by examining three specific areas: drug metabolism, modulation of endogenous metabolites to assist in therapeutic escape, and changes in protein activity gauged by ATP probe uptake.
Topics: Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Melphalan; Metabolome; Metabolomics; Multiple Myeloma; Proteomics; Tandem Mass Spectrometry
PubMed: 31127562
DOI: 10.1007/978-1-4939-9488-5_21 -
Biology of Blood and Marrow... Dec 2020High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible...
High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible multiple myeloma. The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution, leading to the use of propylene glycol (PG) as a solubilizing agent. A newer PG-free Mel preparation (Evomela) uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single-phase IIb study showing bioequivalence. We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation (PG-Mel) to the newer one (PGF-Mel). Of 294 autoHCT recipients, 162 received PG-Mel conditioning and 132 received PGF-Mel conditioning. The PGF-Mel group was older and had a lower average Karnofsky Performance Status score. PGF-Mel was associated with faster neutrophil recovery (median, 12 days versus 13 days; P < .001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% versus 8.0%; P = .048), and a lower 30-day rehospitalization rate (6.8% versus 17.9%; P = .04), as confirmed by propensity-weighted analysis. No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Transplantation Conditioning; Transplantation, Autologous
PubMed: 32920204
DOI: 10.1016/j.bbmt.2020.08.030 -
The Cochrane Database of Systematic... Dec 2015This is the second update of the review first published in the Cochrane Database of Systematic Reviews in 2009, Issue 1. Epithelial ovarian cancer is diagnosed in over... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is the second update of the review first published in the Cochrane Database of Systematic Reviews in 2009, Issue 1. Epithelial ovarian cancer is diagnosed in over 200,000 women worldwide each year. Ten to 20% of women are diagnosed early, when there is still a good possibility of cure. The treatment of early-stage (stage I and IIa) disease involves surgery to remove the disease, often followed by chemotherapy (adjuvant chemotherapy). The largest clinical trials of adjuvant chemotherapy show an overall survival (OS) advantage with platinum-based chemotherapy; however the precise role and type of this treatment in subgroups of women with differing prognoses needs to be defined.
OBJECTIVES
To undertake a systematic review of the evidence for adjuvant chemotherapy in early-stage epithelial ovarian cancer to determine whether chemotherapy following surgery offers a survival advantage over the policy of observation following surgery (with chemotherapy reserved for treatment of disease recurrence); and to determine if clinical subgroups of women with differing prognoses, based on histological subtype or completeness of surgical staging, have more or less to gain from adjuvant chemotherapy.
SEARCH METHODS
We performed an electronic search using the Cochrane Gynaecological Cancer Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 3), MEDLINE (1948 to March week 5, 2015), and EMBASE (1980 to week 14, 2015). We developed the search strategy using free-text and medical subject headings (MeSH). We also searched registers of clinical trials and citation lists of included studies for potentially relevant studies.
SELECTION CRITERIA
We included randomised clinical trials (RCTs) of women with early stage (I/IIa) epithelial ovarian cancer staged at laparotomy.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed study quality of included RCTs. We resolved any disagreements by discussion with a third review author. We used random-effects methods for all meta-analyses, including subgroup analyses.
MAIN RESULTS
The original version of this Cochrane review included five RCTs involving 1277 women. In this 2015 update, no new studies met the inclusion criteria but we included an additional paper with mature data (10-year follow-up) relating to a previously included study (ICON1).We included four studies in the meta-analyses and considered them to be at a low risk of bias. Most study participants (> 95%) had stage I ovarian cancer. Meta-analysis of five-year data from three studies indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (Hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53 to 0.93; 1008 women; 3 studies; I² statistic = 0%; high quality evidence). Likewise, meta-analysis of five-year data from four studies indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (HR 0.67, 95% CI 0.53 to 0.84; 1170 women, 4 studies; I² statistic = 0%; high quality evidence). These findings were robust over time, with 10-year HR estimates of 0.72 (95% CI 0.57 to 0.92; 925 women, 2 studies) and 0.67 (95% CI 0.53 to 0.83; 925 women, 2 studies) for OS and PFS, respectively (high quality evidence). The risk of death at 10 years follow-up favoured the adjuvant chemotherapy arm (0.76, 95% CI 0.62 to 0.94; 923 women, 2 studies; I² statistic = 0%), as did the findings for risk of progression at 10 years (RR 0.72, 95% CI 0.60 to 0.87; 925 women, 2 studies; I² statistic = 0%). Low quality evidence suggested that women with high-risk disease may have the most to gain from adjuvant chemotherapy. However, subgroup analyses could neither confirm nor exclude survival benefits in lower risk disease or in optimally staged disease. We found insufficient data to compare adverse events and long term risks between chemotherapy and observation groups.
AUTHORS' CONCLUSIONS
High-quality evidence indicates that adjuvant platinum-based chemotherapy is effective in prolonging survival in women with early stage (FIGO stage I/IIa) epithelial ovarian cancer. It remains uncertain whether women with low- and intermediate-risk early stage disease will benefit as much from adjuvant chemotherapy as women with high-risk disease. Decisions to use adjuvant chemotherapy (AC) in these women should be mindful of this uncertainty, and the uncertainty regarding adverse events. Treatment of women with lower risk disease should be individualised to take into account individual factors.
Topics: Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Early Detection of Cancer; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Randomized Controlled Trials as Topic
PubMed: 26676202
DOI: 10.1002/14651858.CD004706.pub5 -
PloS One 2024Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an...
Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.
Topics: Humans; Melphalan; Multiple Myeloma; Cell Line, Tumor; Sulfonamides
PubMed: 38593113
DOI: 10.1371/journal.pone.0299019 -
Internal Medicine Journal Oct 2022Cardiac light chain (AL) amyloidosis is a condition with a very poor prognosis. We report a retrospective analysis comparing the traditional melphalan and dexamethasone...
Cardiac light chain (AL) amyloidosis is a condition with a very poor prognosis. We report a retrospective analysis comparing the traditional melphalan and dexamethasone protocol with cyclophosphamide, bortezomib and dexamethasone in late-stage cardiac AL amyloidosis. The primary end points were overall survival and haematological response. Both regimens provided meaningful responses in this difficult to treat patient group.
Topics: Humans; Bortezomib; Immunoglobulin Light-chain Amyloidosis; Melphalan; Retrospective Studies; Dexamethasone; Amyloidosis; Cyclophosphamide
PubMed: 36266066
DOI: 10.1111/imj.15926 -
Clinical Pharmacology and Therapeutics Sep 2017High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and... (Comparative Study)
Comparative Study Randomized Controlled Trial
High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.
Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Creatinine; Cryotherapy; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Large Neutral Amino Acid-Transporter 1; Male; Melphalan; Middle Aged; Multiple Myeloma; Polymorphism, Genetic; Stomatitis; Survival Rate; Time Factors
PubMed: 28160288
DOI: 10.1002/cpt.644 -
Transplantation and Cellular Therapy Sep 2022The use of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is the standard of care in patients who are deemed transplantation eligible. Novel... (Review)
Review
The use of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is the standard of care in patients who are deemed transplantation eligible. Novel therapies, namely immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, have revolutionized the treatment algorithm for MM but have not yet resulted in a cure. To achieve long-lasting disease control in MM, a high-dose conditioning regimen followed by ASCT continues to be an essential part of the management of transplantation-eligible patients with MM. High-dose (or conditioning) regimens are preparative chemotherapy-based regimens used before ASCT. High-dose melphalan is the most commonly used regimen in MM treatment. This clinical review provides an evidence-based summary to guide practicing hematologists/oncologists in the various high-dose regimens used before ASCT in MM treatment. We highlight the use of single-agent melphalan along with various combination-based high-dose regimens with their clinical efficacy. Various dosing schedules and modifications, timing of administration, and novel drugs-based combination regimens are discussed.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous
PubMed: 35750284
DOI: 10.1016/j.jtct.2022.06.013 -
Turkish Journal of Medical Sciences Aug 2019High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin’s...
BACKGROUND/AIM
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin’s lymphoma (HL) or non-Hodgkin’s lymphoma (NHL). In this study, we report the outcome of the mitoxantrone-melphalan conditioning regimen for lymphoma.
MATERIALS AND METHODS
The study group included 53 patients who were relapsed/refractory HL (n = 14) and NHL (n = 39) and received mitoxantrone and melphalan followed by ASCT. The transplant regimen consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by peripheral blood stem cell infusion (PBSC).
RESULTS
Prior to high-dose chemotherapy, 37.7% of the patients were in complete remission (CR) and 45.3% were in partial remission (PR), and 17% had stable or progressive disease. After high-dose chemotherapy and PBSC, 44 out of 51 patients achieved CR (86.2%). CR was achieved in 24 out of 33 patients (72.7%) who were transplanted in a marginally active phase of the disease. At a median followup of 25.4 months (1.8–131.3 months) after ASCT, 13 patients relapsed/ progressed and 8 patients died. The estimated 2-year overall survival (OS) was 81.9%, and event-free survival (EFS) was 59.3%.
CONCLUSION
High-dose chemotherapy followed by ASCT is an effective conditioning regimen in relapsed/refractory lymphoma patients who are undergoing ASCT.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mitoxantrone; Recurrence; Retrospective Studies; Young Adult
PubMed: 31293116
DOI: 10.3906/sag-1809-36 -
Transplantation and Cellular Therapy Jul 2022Total body irradiation in combination with melphalan for multiple myeloma (MM) has been shown to be prohibitively toxic. To ameliorate toxicity, total marrow irradiation...
Total body irradiation in combination with melphalan for multiple myeloma (MM) has been shown to be prohibitively toxic. To ameliorate toxicity, total marrow irradiation (TMI) has been administered as the sole ablative modality during the second cycle of tandem autologous stem cell transplantation (TASCT) for MM patients on a phase I-II trial. Patients with MM in response or with stable disease and ≤18 months from diagnosis received melphalan 200 mg/m and autologous stem cell transplantation (ASCT) (cycle 1) and then, after recovery, TMI and another ASCT (cycle 2), followed by maintenance with an immunomodulatory drug (ImiD) and dexamethasone for up to 12 months. TMI doses were escalated from 1000 cGy to 1800 cGy in 200-cGy increments. Fifty-four patients were to receive TASCT between 2004 and 2011; 8 patients received single ASCT because of patient or physician preference. The median time between melphalan and TMI was 65 days (range, 47 to 125 days). Thirty patients (55.6%) underwent TASCT at the maximum tolerated dose of 1600 cGy. The complete response and very good partial response rates were 48.1% and 22.2%, respectively, following ASCT and maintenance. The median follow-up among survivors was 12.3 years (range, 9.2 to 15.5+ years). Progression-free survival (PFS) and overall survival at 10 years were 20.4% (95% confidence interval [CI], 10.9% to 31.9%) and 38.8% (95% CI, 25.9% to 51.5%), respectively. Secondary neoplasms included (1 each) acute myelogenous leukemia, papillary thyroid and prostate carcinoma, and melanoma, and there was 1 case of ductal carcinoma in situ and 4 cases of nonmelanoma skin cancers. TMI as part of TASCT was well tolerated, and TASCT was associated with a 20.4% PFS plateau. The inclusion of TMI as a conditioning regiment for MM before ASCT warrants further study in the context of modern induction and maintenance therapies.
Topics: Bone Marrow; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Transplantation, Autologous
PubMed: 35534000
DOI: 10.1016/j.jtct.2022.04.022