Gastric cancer Smyth, Elizabeth C; Nilsson, Magnus; Grabsch, Heike I ...
The Lancet (British edition),
08/2020, Letnik:
396, Številka:
10251
Journal Article
Recenzirano
Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, ...and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
...as expected with an immunogenic, high neoantigen expressing tumour, the 8–10% of patients who are diagnosed with operable MSI tumours have excellent survival with surgery alone. ...neither ...perioperative (MAGIC) nor adjuvant (CLASSIC) chemotherapy improved survival when added to surgery for patients with MSI gastric cancer, a result consistent with in-vitro studies showing chemoresistance in mismatch repair deficient tumours and poor outcomes in patients with advanced MSI gastric cancer treated with chemotherapy. No prospective studies were done to assess the lack of effect of chemotherapy in MSI colon cancer; treatment changed based on translational results from prospective clinical trials similar to the current situation for gastric cancer.
In an earlier interim analysis of the study (n=434), a difference in radiological response rates (74·4% vs 51·9%) was sufficient to achieve interim regulatory approvals in the USA and Asia.5 At the ...second interim analysis, Janjigian and colleagues report a statistically significant reduction in disease progression in the trial population with the addition of pembrolizumab to chemotherapy and trastuzumab (median progression-free survival 10·0 months 95% CI 8·6–12·2 vs 8·1 months 7·1–8·6; hazard ratio (HR) 0·72 95% CI 0·6–0·87; p=0·0002). By contrast, treatment of HER2-positive and PD-L1-negative tumours with immunotherapy might lead to increased toxicity and cost without survival benefit. Use of independent, systematic, well validated assessment tools, such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale, also provide value when assessing the true importance of novel therapies.11 The results from Janjigian and colleagues6 are an advance in gastro-oesophageal adenocarcinoma precision oncology.
...how do we balance the risks and benefits of chemotherapy plus nivolumab versus nivolumab–ipilimumab for patients with oesophageal SCC? ...for most patients, cytotoxic chemoimmunotherapy has a ...direct and more rapid onset of action and clinical benefit than immunotherapy alone. ...in CheckMate-648 around half (52%) of nivolumab–ipilimumab-treated patients had second-line treatment. Since platinum-based chemotherapy is the backbone of systemic therapy for oesophageal SCC, it seems a relevant omission if patients cannot benefit from this treatment. Altered patient performance status, number of metastases, and laboratory findings (such as leukocytosis) were described as poor prognostic indicators and can inform decision making. ...a patient with a good performance status who presents with metachronous lymph node metastases is an ideal candidate for nivolumab–ipilimumab, whereas a patient presenting with multiple synchronous liver and bone metastases should receive chemotherapy.
The advent of ctDNA has the potential to be a game changer in some cancers, but limited data is available in oesophago-gastric cancers (OGC). The prognostic value of ctDNA and the potential for false ...positive results due to clonal haematopoiesis of indeterminate potential (CHIP) was recently reported in operable OGC.
Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer-related mortality. Early detection, aggressive surgical resection, and postoperative ...adjuvant therapy have led to survival improvement for early-stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for antiangiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pretreated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA-approved therapy for advanced gastric cancer after prior chemotherapy.
Surgery represents the only curative approach for resectable gastric cancer. However, rates of recurrence remain high. This review summarizes the state of the art and future perspectives regarding ...perioperative, neoadjuvant and adjuvant chemotherapy for localized gastric cancer with insights regarding precision medicine.
Perioperative chemotherapy with FLOT has significantly improved outcomes for non-Asian patients with resectable gastric cancer, removing the role for anthracyclines. Preliminary results demonstrate that the perioperative approach is an option for Asian patients; however, long-term outcomes are awaited. For adjuvant treatment in Asian gastric cancer patients, S-1 as well as docetaxel may be a new treatment option. In this context, the right selection of patients is crucial. Among several biomarkers, microsatellite instability/mismatch repair deficiency has been linked with a lack of benefit from chemotherapy as well as better prognosis.
Multimodality treatment represents the standard of care for resectable gastric cancer. Perioperative chemotherapy with FLOT is the standard treatment in western countries; in patients who are not suitable for triplet, a platinum-fluoropyrimidine doublet can be considered. In Asian countries, adjuvant chemotherapy based on fluoropyrimidine monotherapy or in association with oxaliplatin/docetaxel are options. Validation of prognostic and predictive biomarkers is needed in order to improve patient selection.
Summary Background Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, ...improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Methods In this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov , number NCT00450203. Findings Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio HR 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 10% of 233 in the chemotherapy alone group vs 52 24% of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). Interpretation The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. Funding Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.
The US Food and Drug Administration has granted regulatory approval for the use of nivolumab-an immune checkpoint inhibitor (ICI)-in the first-line treatment of advanced gastric or esophageal ...adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1-expressing tumors remains unclear.
This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved.
CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio HR = 0.950, 95% CI, 0.747 to 1.209,
= .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236,
= .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635,
< .001).
Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1-expressing GEAC tumors.
The MET/hepatocyte growth-factor (HGF) signaling pathway plays a key role in the processes of embryogenesis, wound healing, and organ regeneration. Aberrant activation of MET/HGF occurs through ...multiple mechanisms including gene amplification, mutation, protein overexpression, and abnormal gene splicing interrupting autocrine and paracrine regulatory feedback mechanisms. In many cancers including non-small-cell lung cancer, colorectal, gastric, renal, and hepatocellular cancer, dysregulation of MET may lead to a more aggressive cancer phenotype and may be a negative prognostic indicator. Successful therapeutic targeting of the MET/HGF pathway has been achieved using monoclonal antibodies against the MET receptor and its ligand HGF in addition to MET-specific and multitargeted small-molecule tyrosine-kinase inhibitors with several drugs in late-phase clinical trials including onartuzumab, rilotumumab, tivantinib, and cabozantinib. MET frequently interacts with other key oncogenic tyrosine kinases including epidermal growth-factor receptor (EGFR) and HER-3 and these interactions may be responsible for resistance to anti-EGFR therapies. Similarly, resistance to MET inhibition may be mediated through EGFR activation, or alternatively by increasing levels of MET amplification or acquisition of novel "gatekeeper" mutations. In order to optimize development of effective inhibitors of the MET/HGF pathway clinical trials must be enriched for patients with demonstrable MET-pathway dysregulation for which robustly standardized and validated assays are required.
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