-
Cancer Chemotherapy and Pharmacology Nov 2021Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand...
PURPOSE
Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.
METHODS
A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.
RESULTS
Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study.
CONCLUSION
It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.
Topics: Antineoplastic Agents, Alkylating; DNA Adducts; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Melphalan; Neoplasms; Pharmacogenomic Variants; Progression-Free Survival; Treatment Outcome
PubMed: 34347127
DOI: 10.1007/s00280-021-04340-z -
Clinical Hematology International 2024Globally, multiple myeloma (MM) ranks 24 among the most common cancers. The Middle East and Africa are affected by an increasing trend in MM incidence, owing to several...
BACKGROUND
Globally, multiple myeloma (MM) ranks 24 among the most common cancers. The Middle East and Africa are affected by an increasing trend in MM incidence, owing to several underlying factors. This systematic review aims to assess the epidemiology, patient characteristics, and treatment outcomes associated with MM in selected countries in the Middle East and Africa.
METHODS
An electronic search was performed in the PubMed/MEDLINE database. Abstracts presented at the annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology and the GLOBOCAN registry were searched. Qualitative analysis was performed.
RESULTS
A total of 412 articles were screened, and 14 were selected. The five-year prevalence per 100,000 gathered from country-wise GLOBOCAN data ranged between 155 in Kuwait and 5,625 in North Africa. The identified treatment options were proteasome inhibitors such as bortezomib, drugs such as thalidomide, lenalidomide, dexamethasone, melphalan, and cyclophosphamide, and newer drugs such as daratumumab.
CONCLUSION
Improved diagnostic capability has increased the incidence of MM in this region. However, advanced drugs and treatment regimens remain unaffordable in many countries of these regions. Therefore, understanding the trends of the disease and improving healthcare settings are imperative.
PubMed: 38817690
DOI: 10.46989/001c.92555 -
Oncotarget Jul 2016We performed a network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy of several intravesical chemotherapeutic (IVC) agents after... (Meta-Analysis)
Meta-Analysis Review
Single, immediate postoperative instillation of chemotherapy in non-muscle invasive bladder cancer: a systematic review and network meta-analysis of randomized clinical trials using different drugs.
We performed a network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy of several intravesical chemotherapeutic (IVC) agents after transurethral resection of bladder tumor (TURB) in non-muscle invasive bladder cancer patients. The literature search was conducted using the Embase, Scopus and PubMed databases for RCTs, including patients with single or multiple, primary or recurrent stage Ta or T1 urothelial carcinoma of the bladder managed with a single, immediate instillation of IVC after TURB. Thirteen RCTs met the eligibility criteria. Pair-wise meta-analysis (direct comparison) showed that pirarubicin [hazard ratio (HR): 0.31], epirubicin (HR: 0.62), and MMC (HR: 0.40) were the most effective drugs for reducing tumor recurrence. Bayesian network meta-analysis (indirect comparison) revealed that treatment with pirarubicin (HR: 0.31), MMC (HR: 0.44), or epirubicin (HR: 0.60) was associated with prolonged recurrence-free survival. Among the drugs examined, only pirarubicin reduced disease progression compared to controls. These results suggest that a single, immediate administration of IVC with pirarubicin, MMC, or epirubicin is associated with prolonged recurrence-free survival following TURB in non-muscle invasive bladder cancer patients, though only pirarubicin also reduced disease progression.
Topics: Administration, Intravesical; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cyclophosphamide; Doxorubicin; Epirubicin; Humans; Melphalan; Network Meta-Analysis; Semustine; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 27323781
DOI: 10.18632/oncotarget.9991 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2019Many new regimens have been applied to newly diagnosed transplant-ineligible multiple myeloma, but no head-to-head research has been performed to compare the efficacy of... (Meta-Analysis)
Meta-Analysis
Many new regimens have been applied to newly diagnosed transplant-ineligible multiple myeloma, but no head-to-head research has been performed to compare the efficacy of these treatments. Currently lenalidomide plus dexamethasone (Rd) is one of the standard treatments. Our aim was to make a comparison of these treatments to Rd by a network meta-analysis. We performed a systematic review and network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for articles published from January 1, 1988, to April 26, 2018, as well as research presented at 5 international conferences (American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, European Society of Medical Oncology, and International Myeloma Working Group) between January 2015 and December 2018. Our interest outcomes were hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Bayesian fixed-effects mixed-treatment comparisons were used for this study. A total of 23 articles describing 10,401 participants were included for this network meta-analysis. Lenalidomide and dexamethasone plus daratumumab (HR, 0.57; 95% credible interval [CrI], 0.43-0.73), daratumumab plus bortezomib, melphalan, and prednisone (HR, 0.59; 95% CrI, 0.36-0.91), and the combination of bortezomib with lenalidomide and dexamethasone (RVd) (HR, 0.72, 95% CrI, 0.56-0.90) all showed significant effect compared to Rd for PFS. RVd demonstrated significant benefit compared to Rd (HR, 0.72; 95% CrI, 0.53-0.96) for OS. Our study results suggested that lenalidomide and dexamethasone plus daratumumab; daratumumab plus bortezomib, melphalan, and prednisone; and RVd showed better efficacy than Rd in PFS; and RVd showed better efficacy than Rd in OS in patients with newly diagnosed transplant-ineligible multiple myeloma in the absence of head-to-head research.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Thalidomide; Treatment Outcome
PubMed: 31130487
DOI: 10.1016/j.clml.2019.04.009 -
The Cochrane Database of Systematic... Apr 2009Gestational trophoblastic disease (GTD) includes gestational trophoblastic tumour and hydatidiform mole. Many women of reproductive age are affected by this disease... (Review)
Review
BACKGROUND
Gestational trophoblastic disease (GTD) includes gestational trophoblastic tumour and hydatidiform mole. Many women of reproductive age are affected by this disease although its incidence differs by geographical location. A number of chemotherapy regimens are used for treating the disease, such as methotrexate, actinomycin D and cyclophosphamide (MAC), methotrexate, actinomycin D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine (CHAMOC), etoposide, methotrexate and actinomycin (EMA) plus cyclophosphamide and vincristine (CO) (EMA-CO), etoposide, methotrexate and actinomycin (EMA) plus etoposide and cisplatin(EP) (EMA-EP). The efficacy of these drugs has not been systematically reviewed.
OBJECTIVES
To determine the efficacy and safety of combination chemotherapy in treating high-risk GTT.
SEARCH STRATEGY
Electronic searches of Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2008), MEDLINE, EMB and CBM, May 2008. Four journals were handsearched and other searching methods were used for identifying more studies.
SELECTION CRITERIA
The review included randomised controlled trials (RCTs) or quasi-RCTs of combination chemotherapy for treating high-risk GTT. Patients with placental-site trophoblastic tumour (PSTT), who had received chemotherapy in the previous two weeks, or patients with chemotherapy intolerance were excluded.
DATA COLLECTION AND ANALYSIS
Two investigators independently collected data using a data extraction form. Meta-analysis was not performed and the review was conducted as a narrative review.
MAIN RESULTS
One study with 42 participants was included in this review. It indicated that a MAC regimen was better than a CHAMOCA regimen for high-risk GTT because of lower toxicity. The quality of the study was unclear.
AUTHORS' CONCLUSIONS
The methodological limitations of the included study prevent any firm conclusions about the best combination chemotherapy regimen for high-risk GTT. High quality studies are required.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Gestational Trophoblastic Disease; Humans; Hydatidiform Mole; Hydroxyurea; Melphalan; Methotrexate; Pregnancy; Trophoblastic Tumor, Placental Site; Vincristine
PubMed: 19370618
DOI: 10.1002/14651858.CD005196.pub3 -
Journal of Neurointerventional Surgery Dec 2019Intra-arterial chemotherapy for retinoblastoma has been adopted as a first-line treatment option by numerous tertiary centers. The effect of intra-arterial chemotherapy... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Intra-arterial chemotherapy for retinoblastoma has been adopted as a first-line treatment option by numerous tertiary centers. The effect of intra-arterial chemotherapy on future rates of metastatic disease as well as on globe salvage in advanced eyes remains relatively unknown.
METHODS
A search of PubMED, MEDLINE, EMBASE, and Web of Science electronic databases was conducted from inception until January 2019 for studies with a minimum of 10 patients reporting outcomes and complications following intra-arterial chemotherapy for retinoblastoma.
RESULTS
A total of 20 studies met the inclusion criteria for analysis, comprising 873 patients and 1467 eyes. Only one study was comparative; there was substantial heterogeneity in reported outcomes and several overlapping patient cohorts that were published. Across all studies, 174 of 1467 eyes were enucleated (11.8%). Metastatic disease occurred in 8 of 513 patients (1.6%). Globe salvage was achieved in 318 of 906 (35.6%) cases of advanced retinoblastoma. The most common ocular complication was retinal detachment, occurring in 23% of eyes, and the most common systemic complications were transient fever and nausea/vomiting.
CONCLUSIONS
There is a paucity of higher-level evidence with adequate follow-up surrounding the long-term safety of intra-arterial chemotherapy and effect on metastasis in retinoblastoma. Studies to date have been limited by short-term follow-up. Longitudinal prospective studies could provide greater insight into the ability of intra-arterial chemotherapy to reduce the risk of retinoblastoma metastasis.
Topics: Antineoplastic Agents; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy
PubMed: 31103993
DOI: 10.1136/neurintsurg-2019-014909 -
ClinicoEconomics and Outcomes Research... 2016To review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of... (Review)
Review
OBJECTIVES
To review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of BTZ.
METHODS
Literature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER) were adjusted by 2014 country-specific gross domestic product per capita (GDPPC) to compare the cost-effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]).
RESULTS
A total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT) in Canada, Poland, and Germany (ICER per QALY: 0.9299-2.254 GDPPC). BTZ/melphalan/prednisolone (VMP) was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP), melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD) (ICER per QALY: dominant to 2.374 GDPPC) in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317-1.8210 GDPPC) in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY), and dexamethasone (DEX) in four Nordic countries (€54,451-€81,560/QALY). However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT) and continuous lenalidomide (LEN) plus low-dose DEX (RD) for previously untreated and SCT-ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias associated with model design and the indirect comparisons of treatment effects.
CONCLUSION
Published CEAs suggested that BTZ or BTZ-containing regimens were cost-effective when compared to most non-BTZ treatments for MM. However, the conflicting cost-effectiveness for VMP versus MPT for previously untreated and SCT-ineligible MM and BTZ versus LEN/DEX for relapsed/refractory MM needs more robust evidence for further clarification.
PubMed: 27217786
DOI: 10.2147/CEOR.S104195 -
Metabolism: Clinical and Experimental Sep 2022Several anticancer agents have been associated with cardiac toxic effects. The currently proposed mechanisms to explain cardiotoxicity differ among anticancer agents,... (Review)
Review
Several anticancer agents have been associated with cardiac toxic effects. The currently proposed mechanisms to explain cardiotoxicity differ among anticancer agents, but in fact, the specific modulation is not completely elucidated. Thus, this systematic review aims to provide an integrative perspective of the molecular mechanisms underlying the toxicity of anticancer agents on heart muscle while using a high-throughput technology, mass spectrometry (MS)-based proteomics. A literature search using PubMed database led to the selection of 27 studies, of which 13 reported results exclusively on animal models, 13 on cardiomyocyte-derived cell lines and only one included both animal and a cardiomyocyte line. The reported anticancer agents were the proteasome inhibitor carfilzomib, the anthracyclines daunorubicin, doxorubicin, epirubicin and idarubicin, the antimicrotubule agent docetaxel, the alkylating agent melphalan, the anthracenedione mitoxantrone, the tyrosine kinase inhibitors (TKIs) erlotinib, lapatinib, sorafenib and sunitinib, and the monoclonal antibody trastuzumab. Regarding the MS-based proteomic approaches, electrophoretic separation using two-dimensional (2D) gels coupled with tandem MS (MS/MS) and liquid chromatography-MS/MS (LC-MS/MS) were the most common. Overall, the studies highlighted 1826 differentially expressed proteins across 116 biological processes. Most of them were grouped in larger processes and critically analyzed in the present review. The selection of studies using proteomics on heart muscle allowed to obtain information about the anticancer therapy-induced modulation of numerous proteins in this tissue and to establish connections that have been disregarded in other studies. This systematic review provides interesting points for a comprehensive understanding of the cellular cardiotoxicity mechanisms of different anticancer drugs.
Topics: Animals; Antineoplastic Agents; Cardiotoxicity; Chromatography, Liquid; Proteomics; Tandem Mass Spectrometry
PubMed: 35809654
DOI: 10.1016/j.metabol.2022.155250 -
The Cochrane Database of Systematic... Jan 2013This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear.
OBJECTIVES
To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN.
SEARCH METHODS
For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012. In addition, we searched online clinical trial registries for ongoing trials.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN.
DATA COLLECTION AND ANALYSIS
Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study.
MAIN RESULTS
We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens.
AUTHORS' CONCLUSIONS
CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dactinomycin; Doxorubicin; Early Termination of Clinical Trials; Female; Gestational Trophoblastic Disease; Humans; Hydatidiform Mole; Hydroxyurea; Leucovorin; Melphalan; Methotrexate; Pregnancy; Trophoblastic Tumor, Placental Site; Vincristine
PubMed: 23440800
DOI: 10.1002/14651858.CD005196.pub4 -
The Cochrane Database of Systematic... Jan 2009Waldenstrom's macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder characterized by bone marrow infiltration and production of monoclonal... (Review)
Review
BACKGROUND
Waldenstrom's macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder characterized by bone marrow infiltration and production of monoclonal immunoglobulin. Uncertainty remains if alkylating agents, such as chlorambucil, melphalan or cyclophosphamide, are an effective form of management.
OBJECTIVES
To assess the effects and safety of the alkylating agents on Waldenstrom's macroglobulinaemia (WM).
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2008), MEDLINE (1966 to 2008), EMBASE (1980 to 2008), the Chinese Biomedical Base (1982 to 2008) and reference lists of articles.We also handsearched relevant conference proceedings from 1990 to 2008.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing alkylating agents given concomitantly with radiotherapy, splenectomy, plasmapheresis, stem-cell transplantation in patients with a confirmed diagnosis of WM.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials.
MAIN RESULTS
One trial involving 92 participants with pretreated/relapsed WM compared the effect of fludarabine versus the combination of cyclophosphamide (the alkylating agent), doxorubicin and prednisone (CAP). Compared to CAP, the Hazard ratio (HR) for deaths of treatment with fludarabine was estimated to be 1.04, with a standard error of 0.30 (95% CI 0.58 to 1.48) and it indicated that the mean difference of median survival time was -4.00 months, and 16.00 months for response duration. The relative risks (RR) of response rate was 2.80 (95% CI 1.10 to 7.12). There were no statistically difference in overall survival rate and median survival months, while on the basis of response rate and response duration, fludarabine seemed to be superior to CAP for pretreated/relapsed patients with macroglobulinaemia.
AUTHORS' CONCLUSIONS
Although alkylating agents have been used for decades they have never actually been tested in a proper randomised trial. This review demonstrated that there is currently no evidence to suggest that alkylating agents are effective in treating Waldenstrom's macroglobulinaemia.
Topics: Alkylating Agents; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Prednisone; Randomized Controlled Trials as Topic; Vidarabine; Waldenstrom Macroglobulinemia
PubMed: 19160296
DOI: 10.1002/14651858.CD006719.pub3