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Targeted Oncology Mar 2024Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT.
OBJECTIVE
The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy.
PATIENTS AND METHODS
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity.
RESULTS
Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce.
CONCLUSIONS
Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.
Topics: Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Neoplasm Recurrence, Local; Neuroblastoma; Recurrence; Stem Cell Transplantation
PubMed: 38401028
DOI: 10.1007/s11523-024-01033-4 -
Transplantation and Cellular Therapy Jul 2021Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation... (Meta-Analysis)
Meta-Analysis
Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
Topics: Adolescent; Hematopoietic Stem Cell Transplantation; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation
PubMed: 33798768
DOI: 10.1016/j.jtct.2021.03.026 -
Transplantation and Cellular Therapy Jan 2021The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this...
Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy.
The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
Topics: Adult; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Transplantation Conditioning; Transplantation, Homologous; United States
PubMed: 32966881
DOI: 10.1016/j.bbmt.2020.09.020 -
Annals of Oncology : Official Journal... Dec 2019Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a... (Meta-Analysis)
Meta-Analysis
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.
Topics: Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Drug; Humans; Interleukin-2; Lymphocytes, Tumor-Infiltrating; Melanoma; Recombinant Proteins; Remission Induction; Skin Neoplasms; Transplantation, Autologous; Melanoma, Cutaneous Malignant
PubMed: 31566658
DOI: 10.1093/annonc/mdz398 -
A systematic review of re-induction chemotherapy for children with relapsed high-risk neuroblastoma.European Journal of Cancer (Oxford,... Apr 2019Despite aggressive multimodal therapy, >50% of children with high-risk neuroblastoma (HRNB) relapse. Survival after relapse is rare, and no consensus currently exists on...
BACKGROUND
Despite aggressive multimodal therapy, >50% of children with high-risk neuroblastoma (HRNB) relapse. Survival after relapse is rare, and no consensus currently exists on the most effective therapy.
OBJECTIVE
To conduct a systematic review of the literature on effectiveness of re-induction chemotherapy in children with relapsed HRNB.
METHODS
Database searches were performed to identify studies looking at response to 1st line chemotherapy for children >12 months at diagnosis with first relapse of HRNB. Studies not reporting separate outcomes for HRNB patients or of refractory patients only were excluded. Two independent reviewers extracted the data and assessed study quality using a modified Newcastle-Ottawa tool.
RESULTS
Nine studies were identified fitting the inclusion criteria. All except one were single arm cohorts, and two were retrospective database reviews from single centres. One was a multicentre randomised controlled trial. All used a version of the validated International Neuroblastoma Response Criteria with 8 recording best ever response and 1 at a specified time, and 5 had central review. The proportion of relapsed patients varied from 24 to 100% with 30-93% receiving upfront myeloablative therapy. The response rate varied from 6 to 64%; however, because of heterogeneity, studies were not directly comparable, and no single treatment emerged as the most effective re-induction therapy.
CONCLUSIONS
To date, there is no clear superior re-induction therapy for 1st relapse of HRNB. Randomised controlled trials with separate arms for relapsed versus refractory disease are needed to determine optimal re-induction chemotherapy to act as a backbone for testing newer targeted agents.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Induction Chemotherapy; Infant; Male; Neoplasm Recurrence, Local; Neuroblastoma
PubMed: 30822684
DOI: 10.1016/j.ejca.2018.12.032 -
JAMA Oncology Mar 2018The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction.
OBJECTIVE
To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT.
DATA SOURCES
We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: "myeloma" combined with "autologous," "transplant," "myeloablative," or "stem cell."
STUDY SELECTION
Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis.
DATA EXTRACTION AND SYNTHESIS
For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs.
MAIN OUTCOMES AND MEASURES
The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes.
RESULTS
A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%).
CONCLUSIONS AND RELEVANCE
The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Dexamethasone; Drugs, Investigational; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Multiple Myeloma; Neoadjuvant Therapy; Network Meta-Analysis; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Transplantation, Autologous; Treatment Outcome
PubMed: 29302684
DOI: 10.1001/jamaoncol.2017.4600 -
The Cochrane Database of Systematic... Dec 2015Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high risk patients. Ulceration can lead to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high risk patients. Ulceration can lead to severe pain and difficulty eating and drinking, which may necessitate opioid analgesics, hospitalisation and nasogastric or intravenous nutrition. These complications may lead to interruptions or alterations to cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Oral cryotherapy is a low-cost, simple intervention which is unlikely to cause side-effects. It has shown promise in clinical trials and warrants an up-to-date Cochrane review to assess and summarise the international evidence.
OBJECTIVES
To assess the effects of oral cryotherapy for preventing oral mucositis in patients with cancer who are receiving treatment.
SEARCH METHODS
We searched the following databases: the Cochrane Oral Health Group Trials Register (to 17 June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 5), MEDLINE via Ovid (1946 to 17 June 2015), EMBASE via Ovid (1980 to 17 June 2015), CANCERLIT via PubMed (1950 to 17 June 2015) and CINAHL via EBSCO (1937 to 17 June 2015). We searched the US National Institutes of Health Trials Registry, and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching databases.
SELECTION CRITERIA
We included parallel-design randomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment. We used outcomes from a published core outcome set registered on the COMET website.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. We contacted study authors for information where feasible. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random-effects meta-analyses. We reported adverse effects in a narrative format.
MAIN RESULTS
We included 14 RCTs analysing 1280 participants. The vast majority of participants did not receive radiotherapy to the head and neck, so this review primarily assesses prevention of chemotherapy-induced oral mucositis. All studies were at high risk of bias. The following results are for the main comparison: oral cryotherapy versus control (standard care or no treatment). Adults receiving fluorouracil-based (5FU) chemotherapy for solid cancersOral cryotherapy probably reduces oral mucositis of any severity (RR 0.61, 95% CI 0.52 to 0.72, 5 studies, 444 analysed, moderate quality evidence). In a population where 728 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 444 (95% CI 379 to 524). The number needed to treat to benefit one additional person (NNTB), i.e. to prevent them from developing oral mucositis, is 4 people (95% CI 3 to 5).The results were similar for moderate to severe oral mucositis (RR 0.52, 95% CI 0.41 to 0.65, 5 studies, 444 analysed, moderate quality evidence). NNTB 4 (95% CI 4 to 6).Severe oral mucositis is probably reduced (RR 0.40, 95% CI 0.27 to 0.61, 5 studies, 444 analysed, moderate quality evidence). Where 300 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 120 (95% CI 81 to 183), NNTB 6 (95% CI 5 to 9). Adults receiving high-dose melphalan-based chemotherapy before haematopoietic stem cell transplantation (HSCT)Oral cryotherapy may reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35 to 1.01, 5 studies, 270 analysed, low quality evidence). Where 824 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 486 (95% CI reduced to 289 to increased to 833). The NNTB is 3, although the uncertainty surrounding the effect estimate means that the 95% CI ranges from 2 NNTB, to 111 NNTH (number needed to treat in order to harm one additional person, i.e. for one additional person to develop oral mucositis).The results were similar for moderate to severe oral mucositis (RR 0.43, 95% CI 0.17 to 1.09, 5 studies, 270 analysed, low quality evidence). NNTB 3 (95% CI 2 NNTB to 17 NNTH).Severe oral mucositis is probably reduced (RR 0.38, 95% CI 0.20 to 0.72, 5 studies, 270 analysed, moderate quality evidence). Where 427 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 162 (95% CI 85 to 308), NNTB 4 (95% CI 3 to 9).Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance, and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies.There was limited or no evidence on the secondary outcomes of this review, or on patients undergoing other chemotherapies, radiotherapy, targeted therapy, or on comparisons of oral cryotherapy with other interventions or different oral cryotherapy regimens. Therefore no further robust conclusions can be made. There was also no evidence on the effects of oral cryotherapy in children undergoing cancer treatment.
AUTHORS' CONCLUSIONS
We are confident that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers. We are less confident in the ability of oral cryotherapy to reduce oral mucositis in adults receiving high-dose melphalan before HSCT. Evidence suggests that it does reduce oral mucositis in these adults, but we are less certain about the size of the reduction, which could be large or small. However, we are confident that there is an appreciable reduction in severe oral mucositis in these adults.This Cochrane review includes some very recent and currently unpublished data, and strengthens international guideline statements for adults receiving the above cancer treatments.
Topics: Adult; Antineoplastic Agents; Cryotherapy; Fluorouracil; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Mouth Diseases; Myeloablative Agonists; Neoplasms; Pain; Randomized Controlled Trials as Topic; Stomatitis
PubMed: 26695736
DOI: 10.1002/14651858.CD011552.pub2 -
The Cochrane Database of Systematic... Oct 2015Autologous stem cell transplantation is widely used to restore functioning bone marrow in people with malignant lymphoma or multiple myeloma after myeloablative... (Meta-Analysis)
Meta-Analysis Review
Additional plerixafor to granulocyte colony-stimulating factors for haematopoietic stem cell mobilisation for autologous transplantation in people with malignant lymphoma or multiple myeloma.
BACKGROUND
Autologous stem cell transplantation is widely used to restore functioning bone marrow in people with malignant lymphoma or multiple myeloma after myeloablative chemotherapy. Results of some clinical trials indicate that plerixafor in addition to granulocyte colony-stimulating factors (G-CSF) compared to G-CSF only could lead to an increased mobilisation and release of CD34-positive cells, facilitating effective apheresis.
OBJECTIVES
To evaluate the efficacy and safety of additional plerixafor to G-CSF for haematopoietic stem cell mobilisation in people with malignant lymphoma or multiple myeloma.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1990 to September 2015), as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; American Society for Blood and Marrow Transplantation; European Group for Blood and Marrow Transplantation) for studies. Two review authors independently screened search results.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing plerixafor in addition to G-CSF compared to G-CSF only for stem cell mobilisation in people with malignant lymphoma or multiple myeloma of all stages and ages. We included full text as well as abstracts and unpublished data if sufficient information on study design, participant characteristics, interventions, and outcomes was available. We excluded cross-over trials, quasi-randomised trials, and post-hoc retrospective trials.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the results of the search strategies, extracted data, assessed quality, and analysed data according to standard Cochrane methods. We performed final interpretation with an experienced clinician.
MAIN RESULTS
We identified four RCTs fitting the inclusion criteria. However, two of these closed prematurely due to low recruitment and did not report results. The remaining two trials evaluated 600 participants with multiple myeloma or non-Hodgkin lymphoma. In both studies the experimental group received G-CSF plus plerixafor and the control group received G-CSF plus placebo.The meta-analysis showed no evidence for differences between plerixafor and placebo group regarding mortality at 12 months (600 participants; risk ratio (RR) 1.00, 95% confidence interval (CI) 0.59 to 1.69; P = 1.00; moderate-quality evidence) and adverse events during stem cell mobilisation and collection (593 participants; RR 1.02, 95% CI 0.99 to 1.06; P = 0.19; high-quality evidence).Regarding the outcome successful stem cell collection, the meta-analysis showed an advantage for those participants randomised to the plerixafor group (600 participants; RR 2.42, 95% CI 1.98 to 2.96; P < 0.00001; high-quality evidence).As there was high heterogeneity between studies for the number of transplanted participants, we did not meta-analyse these data. In the multiple myeloma study, 95.9% (142 participants) in the plerixafor arm and 88.3% (136 participants) in the placebo arm underwent transplantation (RR 1.09, 95% CI 1.02 to 1.16); in the non-Hodgkin lymphoma trial, 90% (135 participants) in the plerixafor group versus 55.4% (82 participants) in the placebo group could be transplanted (RR 1.62, 95% CI 1.39 to 1.89). In both trials there was no evidence for a difference between participants in the plerixafor and placebo group in terms of time to neutrophil and platelet engraftment in transplanted participants.None of the trials reported on the outcomes quality of life and progression-free survival.
AUTHORS' CONCLUSIONS
The results of the analysed data suggest that additional plerixafor leads to increased stem cell collection in a shorter time. There was insufficient evidence to determine whether additional plerixafor affects survival or adverse events.The two trials included in the meta-analysis, both of which were conducted by the Genzyme Corporation, the manufacturer of plerixafor, were published several times. Two more RCTs examining the addition of plerixafor to a G-CSF mobilisation regimen terminated early without publishing any outcome. The trials included nine and five participants, respectively. Another RCT with 100 participants was recently completed, but has not yet published outcomes. Due to the unpublished RCTs, it is possible that our review is affected by publication bias, even though two trials failed to recruit a sufficient number of participants to analyse any data.
Topics: Benzylamines; Cyclams; Early Termination of Clinical Trials; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Multiple Myeloma; Randomized Controlled Trials as Topic; Time Factors; Transplantation, Autologous
PubMed: 26484982
DOI: 10.1002/14651858.CD010615.pub2 -
The Cochrane Database of Systematic... Oct 2015Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is the second update of a previously published Cochrane review.
OBJECTIVES
Primary objectiveTo compare the efficacy, that is event-free and overall survival, of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma. Secondary objectivesTo determine adverse effects (e.g. veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies) related to the procedure and possible effects of these procedures on quality of life.
SEARCH METHODS
We searched the electronic databases The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, issue 11), MEDLINE/PubMed (1966 to December 2014) and EMBASE/Ovid (1980 to December 2014). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2014), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2014), Advances in Neuroblastoma Research (ANR) (from 2002 to 2014) and American Society for Clinical Oncology (ASCO) (from 2008 to 2014). We searched for ongoing trials by scanning the ISRCTN register (www.isrct.com) and the National Institute of Health Register (www.clinicaltrials.gov). Both registers were screened in April 2015.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients.
DATA COLLECTION AND ANALYSIS
Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar's method if hazard ratios were not reported in the study. We used a random-effects model.
MAIN RESULTS
We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The first updated search identified a manuscript reporting additional follow-up data for one of these RCTs, while the second update identified an erratum of this study. There was a significant statistical difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (three studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a significant statistical difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (two studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (three studies, 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (two studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any significant statistical differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations.
AUTHORS' CONCLUSIONS
Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow-up. Different risk groups, using the most recent definitions, should be taken into account.It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.
Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Infant; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Randomized Controlled Trials as Topic; Salvage Therapy
PubMed: 26436598
DOI: 10.1002/14651858.CD006301.pub4 -
The Cochrane Database of Systematic... Oct 2011Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT) and allogeneic HCT represent potential treatment alternatives for post-remission therapy... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT) and allogeneic HCT represent potential treatment alternatives for post-remission therapy in adult acute lymphoblastic leukemia (ALL), but there is genuine uncertainty regarding the optimal approach.
OBJECTIVES
To assess the effect of matched sibling donor vs. no donor status for adults with ALL in first complete remission (CR1).
SEARCH STRATEGY
We performed a search of CENTRAL, MEDLINE and EMBASE electronic databases in September 2010 along with handsearching of literature cited in relevant primary articles, search of abstracts from American Society of Hematology and American Society of Clinical Oncology meetings, as well as consultation with content experts in the field.
SELECTION CRITERIA
Review was performed by two authors, and Inclusion criteria included the following: controlled trials with donor vs. no donor comparison with assignment by genetic randomizationin adults with ALL in CR1.
DATA COLLECTION AND ANALYSIS
We extracted data on benefits (overall survival, progression-free survival) and harms (treatment-related mortality, relapse) of compared treatments. Adverse events were considered, but analysis of individual adverse events was not possible from the reported literature. We pooled summary results from each study using a random-effects model. We assessed heterogeneity. We performed subgroup analyses for disease risk categories. We performed sensitivity analyses according to methodological quality.
MAIN RESULTS
A total of 14 relevant trials were identified, consisting of a total of 3157 patients. There was a statistically significant overall survival advantage in favor of the donor versus no donor group (HR 0.86; 95% CI 0.77 to 0.97; P = 0.01), as well as significant improvement in disease-free survival in the donor group(HR 0.82; 95% CI 0.72 to 0.94; P = 0.004). Those in the donor group had significant reduction in primary disease relapse(RR 0.53; 95% CI 0.37 to 0.76; P = 0.0004) and significant increase in non-relapse mortality(RR 2.8; 95% CI 1.66 to 4.73; P = 0.001). Significant heterogeneity was detected in analysis of relapse (Chi(2) 40.51, df = 6, P < 0.00001; I(2) = 85%). In regard to methodologic quality, the majority of included studies were free of selective reporting, and performed analyses according to intention to treat. Conversely, few reported sample size calculation that informed the study design. While blinding was considered as an important domain of methodological quality, none of the studies reported on whether any of the study personnel were blinded (e.g. subjects, personnel, outcome assessors, data analysts etc). Therefore, we did not consider blinding further in the analysis of methodological quality in this review.
AUTHORS' CONCLUSIONS
The results of this systematic review and meta-analysis support matched sibling donor allogeneic hematopoietic cell transplantation as the optimal post-remission therapy in ALL patients aged 15 years or over. This therapy offers superior overall survival and disease-free survival, and significantly reduces the risk of disease relapse, but does impose an increased risk of non-relapse mortality. Importantly these data are based on adult ALL treated with largely total body irradiation-based myeloablative conditioning and sibling donor transplantation and, therefore, cannot be generalized to pediatric ALL, alternative donors including HLA (human leukocyte antigen) mismatched or unrelated donors, or reduced toxicity or non-myeloablative conditioning regimens.
Topics: Adult; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Living Donors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Siblings; Transplantation Conditioning; Transplantation, Homologous
PubMed: 21975786
DOI: 10.1002/14651858.CD008818.pub2