There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
Oncotropic and oncolytic viruses have attracted high attention as antitumor agents because they preferentially kill cancer cells in vitro and reduce the incidence of spontaneous, induced, or ...implanted animal tumors. Some autonomous parvoviruses (H-1, minute virus of mice) and derived recombinant vectors are currently under preclinical evaluation. Still not fully understood, their antitumor properties involve more than just tumor cell killing. Because wild-type parvovirus-mediated tumor cell lysates (TCLs) may trigger antigen-presenting cells (APCs) to augment the host immune repertoire, we analyzed phagocytosis, maturation, and crosspresentation of H-1-induced TCLs by human dendritic cells (DCs). We first established H-1-mediated oncolysis in two HLA-A2(+) and A2(-) variant melanoma cell clones. Monocyte-derived immature DCs phagocytosed H- 1-infected TCLs as well as ultraviolet-induced apoptotic TCLs and better than freeze-thaw-induced necrotic TCLs. Immature DCs incubated with H-1-induced TCLs acquired specific maturation markers comparable to a standard cytokine cocktail. Furthermore, A2(+) DCs pulsed with H-1-infected A2(-) TCLs cross-presented melanoma antigens to specific cytotoxic T lymphocytes (CTLs) and released proinflammatory cytokines. This shows for the first time that tumor cell killing by a wild-type oncolytic virus directly stimulates human APCs and CTLs. Because H-1-infected tumors enhance the immune repertoire, the clinical perspectives of parvoviral vectors are even more promising.
Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased ...delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.
Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).
Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.
The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.
No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.
We ...conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival.
The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval CI, 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group.
Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).
Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic ...outcome characteristics for patients with advanced disease.
Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset.
A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 95% confidence interval (CI) 1.20–2.02} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival HR 2.24 (95% CI 1.53–3.28). In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value 6-month PFS: area under the curve (AUC) 62% (95% CI 57–68); 1-year OS: AUC 64% (95% CI 58–69).
These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.
FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) ...are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.
In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan–Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.
CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n-=-592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P-=-0.051), PFS (P-<-0.001), and OS (P-<-0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.
CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.
The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.
We conducted ...an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.
In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.
Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (
NCT00452569).
On consideration of current medical and socio-economical factors, palliative care is becoming an increasingly important aspect of modern medicine in Germany. The German Society for Digestive and ...Metabolic Disorders (DGVS) has taken this into account by founding the working group "Palliative Gastroenterology". Patients with gastrointestinal malignancies or advanced non-malignant liver disease represent an important group that benefits from palliative care. Approximately 80 % of all palliative care patients suffer from gastrointestinal symptoms and endoscopic procedures performed by gastroenterologists play an important role in relieving symptoms such as obstruction. It is the object of this paper to evaluate the role of gastroenterologists in palliative medicine. It will give a brief definition, a historical review and the current legal background for palliative care in Germany and examine special aspects of ethics, decision making and research. Considering the current evidence on palliative endoscopic procedures this paper wants to establish the role of the gastroenterologist in palliative care far beyond the mere practicalities of endoscopy. The gastroenterologist is a crucial element of the interdisciplinary palliative care team and a partner to the patient in the process of decision-making. Finally, it is demonstrated how palliative care structures can be implemented in the setting of a university acute-care hospital.
PDF
