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The Cochrane Database of Systematic... May 2023Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL).
OBJECTIVES
To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs).
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable.
DATA COLLECTION AND ANALYSIS
All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm.
MAIN RESULTS
We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB.
AUTHORS' CONCLUSIONS
Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.
Topics: Male; Female; Adult; Humans; Carcinoma, Renal Cell; Axitinib; Nivolumab; Network Meta-Analysis; Sunitinib
PubMed: 37146227
DOI: 10.1002/14651858.CD013798.pub2 -
EBioMedicine Apr 2023The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has...
BACKGROUND
The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has spurred interest in using IL-2 for immunotherapy of cancer and autoimmune diseases. Thus, numerous IL-2-based biologic agents with improved bias or delivery towards effector immune cells or Treg cells have been developed. This study systematically reviews clinical results of improved IL-2-based compounds.
METHODS
We searched the ClinicalTrials.gov database for registered trials using improved IL-2-based agents and different databases for available results of these studies.
FINDINGS
From 576 registered clinical trials we extracted 36 studies on different improved IL-2-based compounds. Adding another nine agents reported in recent literature reviews and based on our knowledge totalled in 45 compounds. A secondary search for registered clinical trials of each of these 45 compounds resulted in 141 clinical trials included in this review, with 41 trials reporting results.
INTERPRETATION
So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy.
FUNDING
This work was supported by public funding agencies.
Topics: Humans; Antineoplastic Agents; Interleukin-2; Carcinoma, Renal Cell; Kidney Neoplasms; Immunotherapy; Autoimmune Diseases
PubMed: 37004361
DOI: 10.1016/j.ebiom.2023.104539 -
Biomolecules Jun 2023Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the... (Review)
Review
BACKGROUND
Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear.
METHODS
In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells.
RESULTS
Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration.
CONCLUSIONS
Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.
Topics: Humans; Bone Density Conservation Agents; Bisphosphonate-Associated Osteonecrosis of the Jaw; Denosumab; Diphosphonates; Zoledronic Acid; Angiogenesis Inhibitors
PubMed: 37371553
DOI: 10.3390/biom13060973 -
Frontiers in Pharmacology 2023This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment... (Review)
Review
This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.
PubMed: 37745049
DOI: 10.3389/fphar.2023.1223929 -
Cureus Sep 2022Regorafenib, a multi-kinase inhibitor, has been widely used to treat patients with gastrointestinal stromal tumors (GIST) who failed the initial treatment with imatinib... (Review)
Review
Regorafenib, a multi-kinase inhibitor, has been widely used to treat patients with gastrointestinal stromal tumors (GIST) who failed the initial treatment with imatinib and sunitinib. This systematic review aims to demonstrate the efficacy and safety of regorafenib for patients with metastatic and/or unresectable GIST. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform this systematic review. We searched PubMed, Science Direct, and Cochrane databases to identify relevant articles based on predefined selection criteria. The implication of the search strategy results in 776 records from all databases. We excluded conference abstracts, discussion articles, case reports, case series, systematic reviews, and other observational non-intervention studies from the study, along with the articles published in languages other than English. After the screening and quality assessment, 10 studies were selected for final review - two randomized controlled trials and eight non-randomized prospective and retrospective review articles of intervention. Regorafenib improved the survival rates of patients after the failure of imatinib and sunitinib treatment, with an acceptable safety profile. Close monitoring of the patients may be needed to detect and manage the grade 4 or higher adverse events.
PubMed: 36199644
DOI: 10.7759/cureus.28665 -
Lung Cancer (Amsterdam, Netherlands) Feb 2023Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapse/refractory) face limited therapeutic options given no approved options or... (Meta-Analysis)
Meta-Analysis Review
Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapse/refractory) face limited therapeutic options given no approved options or consensus standard of care. This study aimed to identify and summarize clinical outcomes of all regimens evaluated in clinical trials of relapsed or refractory patients. Interventional trials enrolling advanced TC patients who failed first-line chemotherapy and reported outcomes in this group were eligible for inclusion in our systemic literature review (SLR). Between-study heterogeneity was assessed to determine the feasibility of pooling specific studies and treatments. Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR) endpoints were of interest for meta-analysis. Nineteen trials were identified in the SLR. Three trials with one or two TC patients were removed from our assessment to reduce publication bias. Response rates among studies with at least ten TC patients varied from 9 % to 38 %. Pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28 %, 24 %, and 21 %, respectively. Prolonged duration of response with pembrolizumab was observed with a pooled median of 23.8 months (95 % confidence interval [CI]: 12, not reached). Median PFS of five months or greater was reported in patients treated with sunitinib, lenvatinib, pembrolizumab, capecitabine + gemcitabine, everolimus, or S-1. Median OS of 20 months or greater was reported in trials evaluating S-1 or pembrolizumab; this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Generalizability of treatment effects is challenging in the research of rare diseases and meta-analysis of clinical outcomes may help to increase precision and relevance of results to the larger TC population. Our study found limited treatment options upon relapse, demonstrating a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.
Topics: Humans; Sunitinib; Thymoma; Platinum; Neoplasm Recurrence, Local; Lung Neoplasms; Thymus Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36638588
DOI: 10.1016/j.lungcan.2023.01.003 -
Cancers Mar 2022Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other... (Review)
Review
Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. Oncological therapies have been reported to be a cause of PI as well, but their role is not clearly defined. This systematic review investigates the concurrency of PI and antitumor therapy in cancer patients, considering both solid tumors and onco-hematological ones. We performed a literature review of PubMed, Embase and the Web of Science up to September 2021 according to the PRISMA guidelines. A total of 62 papers reporting 88 different episodes were included. PI was mainly reported with targeted therapies (sunitinib and bevacizumab above all) within the first 12 weeks of treatment. This adverse event mostly occurred in the metastatic setting, but in 10 cases, it also occurred also in the neoadjuvant and adjuvant setting. PI was mostly localized in the large intestine, being fatal in 11 cases, while in the remaining cases, symptoms were usually mild, or even absent. A significant risk of PI reoccurrence after drug reintroduction was also reported (6/18 patients), with no fatal outcomes. Potential pharmacological mechanisms underlying PI pathogenesis are also discussed. In conclusion, although uncommonly, PI can occur during oncological therapies and may lead to life-threatening complications; therefore, consideration of its occurrence among other adverse events is warranted in the presence of clinical suspicion.
PubMed: 35406436
DOI: 10.3390/cancers14071666 -
The Cochrane Database of Systematic... Nov 2021Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete.
OBJECTIVES
To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis.
SEARCH METHODS
We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings.
SELECTION CRITERIA
We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic).
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies.
MAIN RESULTS
We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life).
AUTHORS' CONCLUSIONS
The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.
Topics: Humans; Indoles; Network Meta-Analysis; Pancreatic Neoplasms; Positron-Emission Tomography; Pyrimidines; Radionuclide Imaging; Sulfonamides
PubMed: 34822169
DOI: 10.1002/14651858.CD013700.pub2 -
Journal of Oncology 2022To assess the efficacy and safety of nivolumab for advanced renal cell carcinoma (RCC) via meta-analysis. (Review)
Review
OBJECTIVE
To assess the efficacy and safety of nivolumab for advanced renal cell carcinoma (RCC) via meta-analysis.
METHODS
In this systematic review and meta-analysis, we searched PubMed, Embase, Science Citation Index Expanded, The Cochrane Library, and Web of Science for randomized controlled trials (RCTs) using nivolumab for patients with advanced RCC published before 30 December 2021. Quality assessments and meta-analyses were performed on all the literature assessed for eligibility.
RESULTS
Of 203 studies identified as potentially eligible from 3214 studies in a preliminary search, three RCTs including 2550 RCC cases met the inclusion criteria and were of high quality. Meta-analysis showed benefits of nivolumab in the progression-free survival (PFS) (HR = 0.73, 95% CI: 0.54 to 0.99, =0.04) and overall survival (OS) (HR = 0.70, 95% CI: 0.63 to 0.78, < 0.001) of patients with advanced RCC, and no increase in documented adverse events was recorded.
CONCLUSION
Nivolumab plus ipilimumab has significant benefits versus sunitinib in the treatment of advanced RCC in terms of tumor progression control and prolongation of OS and PFS, with a manageable safety profile.
PubMed: 35368898
DOI: 10.1155/2022/5430525 -
Cureus May 2023In advanced renal cell carcinoma, few randomized controlled trials involving immunotherapy plus antiangiogenic therapy have shown survival benefits relative to... (Review)
Review
Immunotherapy and Antiangiogenic Therapy for the Treatment of Patients With Advanced Renal Cell Carcinoma: A Systematic Review and an Updated Network Meta-Analysis of Phase III Clinical Trials.
In advanced renal cell carcinoma, few randomized controlled trials involving immunotherapy plus antiangiogenic therapy have shown survival benefits relative to Sunitinib. Our meta-analysis aimed to evaluate the efficacy and safety of combined immunotherapy and antiangiogenic therapy compared to Sunitinib therapy alone in patients with advanced renal cell carcinoma. Six phase III randomized controlled trials were analyzed, including 4,119 patients. The primary endpoints were overall survival and progression-free survival, and the secondary endpoints were objective response rate and serious adverse events. The results showed that combined immunotherapy and antiangiogenic therapy significantly improved overall survival, progression-free survival, and objective response rate compared to Sunitinib alone. No significant difference was observed in adverse events between the two groups. This study suggests that combined immunotherapy and antiangiogenic therapy is a great treatment option for advanced renal cell carcinoma.
PubMed: 37303368
DOI: 10.7759/cureus.38838