Background
The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small‐molecule targeted ...drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000.
Objectives
To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma.
Search methods
We searched the following databases up to October 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers and the ASCO database in February 2017, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).
Selection criteria
We considered RCTs of systemic therapies for people with unresectable lymph node metastasis and distant metastatic cutaneous melanoma compared to any other treatment. We checked the reference lists of selected articles to identify further references to relevant trials.
Data collection and analysis
Two review authors extracted data, and a third review author independently verified extracted data. We implemented a network meta‐analysis approach to make indirect comparisons and rank treatments according to their effectiveness (as measured by the impact on survival) and harm (as measured by occurrence of high‐grade toxicity). The same two review authors independently assessed the risk of bias of eligible studies according to Cochrane standards and assessed evidence quality based on the GRADE criteria.
Main results
We included 122 RCTs (28,561 participants). Of these, 83 RCTs, encompassing 21 different comparisons, were included in meta‐analyses. Included participants were men and women with a mean age of 57.5 years who were recruited from hospital settings. Twenty‐nine studies included people whose cancer had spread to their brains. Interventions were categorised into five groups: conventional chemotherapy (including single agent and polychemotherapy), biochemotherapy (combining chemotherapy with cytokines such as interleukin‐2 and interferon‐alpha), immune checkpoint inhibitors (such as anti‐CTLA4 and anti‐PD1 monoclonal antibodies), small‐molecule targeted drugs used for melanomas with specific gene changes (such as BRAF inhibitors and MEK inhibitors), and other agents (such as anti‐angiogenic drugs). Most interventions were compared with chemotherapy. In many cases, trials were sponsored by pharmaceutical companies producing the tested drug: this was especially true for new classes of drugs, such as immune checkpoint inhibitors and small‐molecule targeted drugs.
When compared to single agent chemotherapy, the combination of multiple chemotherapeutic agents (polychemotherapy) did not translate into significantly better survival (overall survival: HR 0.99, 95% CI 0.85 to 1.16, 6 studies, 594 participants; high‐quality evidence; progression‐free survival: HR 1.07, 95% CI 0.91 to 1.25, 5 studies, 398 participants; high‐quality evidence. Those who received combined treatment are probably burdened by higher toxicity rates (RR 1.97, 95% CI 1.44 to 2.71, 3 studies, 390 participants; moderate‐quality evidence). (We defined toxicity as the occurrence of grade 3 (G3) or higher adverse events according to the World Health Organization scale.)
Compared to chemotherapy, biochemotherapy (chemotherapy combined with both interferon‐alpha and interleukin‐2) improved progression‐free survival (HR 0.90, 95% CI 0.83 to 0.99, 6 studies, 964 participants; high‐quality evidence), but did not significantly improve overall survival (HR 0.94, 95% CI 0.84 to 1.06, 7 studies, 1317 participants; high‐quality evidence). Biochemotherapy had higher toxicity rates (RR 1.35, 95% CI 1.14 to 1.61, 2 studies, 631 participants; high‐quality evidence).
With regard to immune checkpoint inhibitors, anti‐CTLA4 monoclonal antibodies plus chemotherapy probably increased the chance of progression‐free survival compared to chemotherapy alone (HR 0.76, 95% CI 0.63 to 0.92, 1 study, 502 participants; moderate‐quality evidence), but may not significantly improve overall survival (HR 0.81, 95% CI 0.65 to 1.01, 2 studies, 1157 participants; low‐quality evidence). Compared to chemotherapy alone, anti‐CTLA4 monoclonal antibodies is likely to be associated with higher toxicity rates (RR 1.69, 95% CI 1.19 to 2.42, 2 studies, 1142 participants; moderate‐quality evidence).
Compared to chemotherapy, anti‐PD1 monoclonal antibodies (immune checkpoint inhibitors) improved overall survival (HR 0.42, 95% CI 0.37 to 0.48, 1 study, 418 participants; high‐quality evidence) and probably improved progression‐free survival (HR 0.49, 95% CI 0.39 to 0.61, 2 studies, 957 participants; moderate‐quality evidence). Anti‐PD1 monoclonal antibodies may also result in less toxicity than chemotherapy (RR 0.55, 95% CI 0.31 to 0.97, 3 studies, 1360 participants; low‐quality evidence).
Anti‐PD1 monoclonal antibodies performed better than anti‐CTLA4 monoclonal antibodies in terms of overall survival (HR 0.63, 95% CI 0.60 to 0.66, 1 study, 764 participants; high‐quality evidence) and progression‐free survival (HR 0.54, 95% CI 0.50 to 0.60, 2 studies, 1465 participants; high‐quality evidence). Anti‐PD1 monoclonal antibodies may result in better toxicity outcomes than anti‐CTLA4 monoclonal antibodies (RR 0.70, 95% CI 0.54 to 0.91, 2 studies, 1465 participants; low‐quality evidence).
Compared to anti‐CTLA4 monoclonal antibodies alone, the combination of anti‐CTLA4 plus anti‐PD1 monoclonal antibodies was associated with better progression‐free survival (HR 0.40, 95% CI 0.35 to 0.46, 2 studies, 738 participants; high‐quality evidence). There may be no significant difference in toxicity outcomes (RR 1.57, 95% CI 0.85 to 2.92, 2 studies, 764 participants; low‐quality evidence) (no data for overall survival were available).
The class of small‐molecule targeted drugs, BRAF inhibitors (which are active exclusively against BRAF‐mutated melanoma), performed better than chemotherapy in terms of overall survival (HR 0.40, 95% CI 0.28 to 0.57, 2 studies, 925 participants; high‐quality evidence) and progression‐free survival (HR 0.27, 95% CI 0.21 to 0.34, 2 studies, 925 participants; high‐quality evidence), and there may be no significant difference in toxicity (RR 1.27, 95% CI 0.48 to 3.33, 2 studies, 408 participants; low‐quality evidence).
Compared to chemotherapy, MEK inhibitors (which are active exclusively against BRAF‐mutated melanoma) may not significantly improve overall survival (HR 0.85, 95% CI 0.58 to 1.25, 3 studies, 496 participants; low‐quality evidence), but they probably lead to better progression‐free survival (HR 0.58, 95% CI 0.42 to 0.80, 3 studies, 496 participants; moderate‐quality evidence). However, MEK inhibitors probably have higher toxicity rates (RR 1.61, 95% CI 1.08 to 2.41, 1 study, 91 participants; moderate‐quality evidence).
Compared to BRAF inhibitors, the combination of BRAF plus MEK inhibitors was associated with better overall survival (HR 0.70, 95% CI 0.59 to 0.82, 4 studies, 1784 participants; high‐quality evidence). BRAF plus MEK inhibitors was also probably better in terms of progression‐free survival (HR 0.56, 95% CI 0.44 to 0.71, 4 studies, 1784 participants; moderate‐quality evidence), and there appears likely to be no significant difference in toxicity (RR 1.01, 95% CI 0.85 to 1.20, 4 studies, 1774 participants; moderate‐quality evidence).
Compared to chemotherapy, the combination of chemotherapy plus anti‐angiogenic drugs was probably associated with better overall survival (HR 0.60, 95% CI 0.45 to 0.81; moderate‐quality evidence) and progression‐free survival (HR 0.69, 95% CI 0.52 to 0.92; moderate‐quality evidence). There may be no difference in terms of toxicity (RR 0.68, 95% CI 0.09 to 5.32; low‐quality evidence). All results for this comparison were based on 324 participants from 2 studies.
Network meta‐analysis focused on chemotherapy as the common comparator and currently approved treatments for which high‐ to moderate‐quality evidence of efficacy (as represented by treatment effect on progression‐free survival) was available (based on the above results) for: biochemotherapy (with both interferon‐alpha and interleukin‐2); anti‐CTLA4 monoclonal antibodies; anti‐PD1 monoclonal antibodies; anti‐CTLA4 plus anti‐PD1 monoclonal antibodies; BRAF inhibitors; MEK inhibitors, and BRAF plus MEK inhibitors. Analysis (which included 19 RCTs and 7632 participants) generated 21 indirect comparisons.
The best evidence (moderate‐quality evidence) for progression‐free survival was found for the following indirect comparisons: • both combinations of immune checkpoint inhibitors (HR 0.30, 95% CI 0.17 to 0.51) and small‐molecule targeted drugs (HR 0.17, 95% CI 0.11 to 0.26) probably improved progression‐free survival compared to chemotherapy; • both BRAF inhibitors (HR 0.40, 95% CI 0.23 to 0.68) and combinations of small‐molecule targeted drugs (HR 0.22, 95% CI 0.12 to 0.39) were probably associated with better progression‐free survival compared to anti‐CTLA4 monoclonal antibodies; • biochemotherapy (HR 2.81, 95% CI 1.76 to 4.51) probably lead to worse progression‐free survival compared to BRAF inhibitors; • the combination of small‐molecule targeted drugs probably improved progression‐free survival (HR 0.38, 95% CI 0.21 to 0.68) compared to anti‐PD1 monoclonal antibodies; • both biochemotherapy (HR 5.05, 95% CI 3.01 to 8.45) and MEK inhibitors (HR 3.16, 95% CI 1.77 to 5.65) were probably associated with worse progression‐free survival compared to the combination of small‐molecule targeted drugs; and • biochemotherapy was probably associated with worse progression‐free survival (HR 2.81, 95% CI 1.54 to 5.11) compared to the combination of immune checkpoint inhibitors.
The best evidence (moderate‐quality evidence) fo
To evade immune destruction, tumors exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumor microenvironment. This is mediated, in part, by amino acid ...degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumor-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine-degrading enzymes by tumor and tumor-infiltrating cells can hamper cancer-specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy.
Colonoscopy remains the gold standard investigation for colorectal cancer screening as it offers the opportunity to both detect and resect pre-malignant and neoplastic polyps. Although technologies ...for image-enhanced endoscopy are widely available, optical diagnosis has not been incorporated into routine clinical practice, mainly due to significant inter-operator variability. In recent years, there has been a growing number of studies demonstrating the potential of convolutional neural networks (CNN) to enhance optical diagnosis of polyps. Data suggest that the use of CNNs might mitigate the inter-operator variability amongst endoscopists, potentially enabling a “resect and discard“ or ”leave in“ strategy to be adopted in real-time. This would have significant financial benefits for healthcare systems, avoid unnecessary polypectomies of non-neoplastic polyps and improve the efficiency of colonoscopy. Here, we review advances in CNN for the optical diagnosis of colorectal polyps, current limitations and future directions.
The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains ...unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.
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•Low arginine condition confers upon activated CD4+ T cells Treg-like properties•Arginine starvation shapes T cell-associated intratumoral immune landscape•The immunosuppression of low arginine educated T cells rely on oxidative metabolism•Low arginine educated T cells keep immunosuppression via ATF4-SLC7A11-GSH axis
Arginine availability shapes T cell fate. Xia and colleagues show that low arginine condition, as present in tumor microenvironments, confers Treg-like immunosuppressive properties upon activated CD4+ T cells via metabolic and transcriptional reprogramming, including keeping active oxidative metabolism and using ATF4-SLC7A11-GSH axis to get rid of the by-product ROS.
Endoscopic submucosal dissection (ESD) has a long learning curve. The aim of this study was to assess the efficacy of an ESD unsupervised training model for experienced endoscopists.
Stepwise ...training included a visit to a high-volume center, unsupervised training on an ex vivo porcine model, and in vivo human upper GI cases with anatomic progression. Performance measures included en bloc resection, R0 resection, adverse event rates, and operating time.
After observation of 30 esophagogastric ESDs and 15 untutored ex vivo ESDs, 5 human cases of distal gastric ESDs were performed, followed by 55 unselected esophagogastric cases. En bloc and R0 resection rates were 93.0% and 80.7%, respectively. Operating time was 14.0 min/cm2 in the stomach and 25.1 min/cm2 in the esophagus, with evidence of a learning curve for esophageal ESDs (first block 30.26 min/cm2 vs second block 14.81 min/cm2, P = .01).
Untutored training for esophagogastric ESD is feasible and allows endoscopists, experienced in therapeutic endoscopy, to achieve the required standards toward competency.
Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the ...literature to gauge the nature and extent of non-infection-related RTX-induced lung disease.
A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes.
A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0-158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases.
ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent.
Background
Since the mid‐2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non‐specific therapy with broad‐acting cytokines to specific regimens, which ...directly target the cancer, the tumour microenvironment, or both.
Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first‐line treatment of people with mRCC and mention non‐specific cytokines as an alternative option for selected patients.
In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death‐1 (PD‐1), was approved as the first specific immunotherapeutic agent as second‐line therapy in previously treated mRCC patients.
Objectives
To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit.
Search methods
We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information.
Selection criteria
We included randomized controlled trials (RCTs) and quasi‐RCTs with or without blinding involving people with mRCC.
Data collection and analysis
We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables.
Main results
We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first‐line (five comparisons) or second‐line therapy (one comparison) for mRCC.
Interferon (IFN)‐α monotherapy probably increases one‐year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate‐quality evidence), may lead to similar quality of life (QoL) (e.g. MD ‐5.58 points, 95% CI ‐7.25 to ‐3.91 for Functional Assessment of Cancer ‐ General (FACT‐G); 1 study; 730 participants; low‐quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low‐quality evidence).
There is probably no difference between IFN‐α plus temsirolimus and temsirolimus alone for one‐year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate‐quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low‐quality evidence). There was no information on QoL.
IFN‐α alone may slightly increase one‐year overall mortality compared to IFN‐α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low‐quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate‐quality evidence). QoL could not be evaluated due to insufficient data.
Treatment with IFN‐α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one‐year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low‐quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low‐quality evidence). QoL could not be evaluated due to insufficient data.
Treatment with vaccines (e.g. MVA‐5T4 or IMA901) or standard therapy may lead to similar one‐year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low‐quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low‐quality evidence). QoL could not be evaluated due to insufficient data.
In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one‐year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate‐quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT‐Kidney Symptom Index Disease Related Symptoms (FKSI‐DRS); 1 study, 704 participants; moderate‐quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate‐quality evidence).
Authors' conclusions
Evidence of moderate quality demonstrates that IFN‐α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low‐quality evidence that IFN‐α alone increases mortality but moderate‐quality evidence on decreased AEs compared to IFN‐α plus bevacizumab. Low‐quality evidence shows no difference for IFN‐α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low‐quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate‐quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.
Esophageal cancer (EC) is among the most frequent and deadly cancers around the world. While esophageal adenocarcinoma (EAC) has one of the fastest-growing incidences amongst cancers in the US, it ...also has one of the lowest survival rates due to the limited effective treatment options. Fortunately, in the past decade, two targeted therapies and an immunotherapy agent have been approved by the FDA for metastatic EAC and esophageal squamous cell carcinoma (ESCC), with several more currently being considered for approval. In terms of immunotherapies, in July 2019, the FDA approved the PD1 inhibitor pembrolizumab for second-line treatment of PDL1-positive, advanced or metastatic ESCC. Two years before, pembrolizumab had been approved for the third-line treatment of PDL1-positive EAC. The PD1 inhibitor nivolumab, which was found in one study to outperform chemotherapy irrespective of PDL1 status, has yet to secure FDA approval. In terms of targeted therapies, although as many as 90% of EC cases show upregulated EGFR, anti-EGFR therapy has not been shown to improve survival. Ramucirumab, an antibody targeting both VEGF and HER2/neu receptors, has been approved for the treatment of refractory EAC, while the anti-HER2 monoclonal antibody (mAb) trastuzumab has been approved as front-line treatment for HER2-positive cases which account for approximately 20% of ECs. Although these targeted therapies and immunotherapies have resulted in significant improvements in survival for specific patient populations that are positive for certain biomarkers, such as PDL1 and HER2/neu, the survival rates remain low for a large proportion of the metastatic EC patient population, necessitating the development of further targeted treatment options.
Gastric intestinal metaplasia (GIM) and gastric atrophy (GA) are associated with increased risk of gastric cancer and are indications for endoscopic surveillance when affecting the proximal stomach.1 ...Endoscopic screening is not cost-effective in areas with low-moderate incidence of gastric cancer2; noninvasive methods to detect GIM/GA are currently lacking.3
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