Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared ...the FDA-approved Cobas® EGFR Mutation Test v2 with the UltraSEEK™ Lung Panel on the MassARRAY® System on detection of EGFR mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ® Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas® and UltraSEEK™ tests. Liquid IQ® analysis was initially validated (n = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ® results were applied to harmonize ccfDNA input for the Cobas® and UltraSEEK™ tests for 63 NSCLC patients. The overall concordance between the Cobas® and UltraSEEK™ tests was 86%. The Cobas® test detected more EGFR exon19 deletions and L858R mutations, while the UltraSEEK™ test detected more T790M mutations. A 100% concordance in both the clinical (n = 137) and harmonized (n = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ® Panel. The Cobas® and UltraSEEK™ tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non–small-cell lung cancer (nsNSCLC).
In this multicentre, ...open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671.
One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel 5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval CI: 0·44–0·86); p = 0·005. Objective response rates (ORRs) were 22·5% (95% CI: 14·8–30·3) and 5·5% (95% CI: 0·0–11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group).
Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population.
ClinicalTrials.gov Identifier: NCT01763671.
•Prognosis of patients with advanced non–small-cell lung cancer (NSCLC) is poor.•Few options beyond platinum-based chemo and immunotherapy in non-squamous (ns) NSCLC.•Phase III trial of bevacizumab-paclitaxel (wPB) or docetaxel in 2nd/3rd line nsNSCLC.•wPB improved progression-free survival and objective response rate.•Safety profile was manageable and Quality of Life was preserved with wPB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To assess the safety and to obtain preliminary data on the efficacy of the three-drug combination chemotherapy with gemcitabine, oxaliplatin and vinorelbine in patients with metastatic bladder ...cancer.
Patients with metastatic or locally unresectable advanced bladder cancer who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received intravenous gemcitabine 700 mg/m(2) and vinorelbine 25 mg/m(2) on day 1, then intravenous oxaliplatin 85 mg/m(2) on day 2, every 14 days.
Fifteen patients were enrolled. Twelve patients were unfit for cisplatin. A median of five cycles per patient were delivered. The most common toxicities were neutropenia, nausea and vomiting, mucositis and diarrhoea. Two complete responses and one partial response were observed for an overall response rate of 23%. Median progression-free survival was 5.7 months and overall survival was 8.6 months.
Although active and tolerable, the described three-drug combination chemotherapy showed no obvious incremental increase in efficacy compared with two-drug regimens. Further clinical trials are not recommended.
The use of a combination of G-CSF and GM-CSF versus G-CSF alone, after cyclophosphamide (4 g/m2) was compared in two randomized phase III studies, including 120 patients. In study A, 60 patients ...received 5 x 2 microg/kg/day of G-CSF and GM-CSF compared to 5 mug/kg/day of G-CSF. In study B, 60 patients received 2.5 x 2 microg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 microg/kg/day). With the aim to collect at least 5 x 10(6)/kg CD34 cells in a maximum of three large volume leukapherises (LK), 123 LK were performed in study A, showing a significantly higher number of patients reaching 10 x 10(6)/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P=0.00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P=0.003). In both the study, the total harvest of CD34 cells/kg was twofold higher in G-CSF plus GM-CSF group (18.3 x 10(6) in study A and 15.85 x 10(6) in study B) than in G-CSF group (9 x 10(6) in study A and 8.1 x 10(6) in study B), a significant difference only seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The prognosis of patients with carcinoma of unknown primary remains poor with an expected median survival of 6 to 12 months. We evaluated the activity of a chemotherapy regimen combining gemcitabine ...and docetaxel in patients who primarily failed cisplatin-based chemotherapy.
Fifteen patients received cycles of gemcitabine 1,000 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 every 3 weeks.
The median number of cycles per patient was 3. Overall toxicity was moderate. Four partial responses were observed among 14 patients with measurable disease. The median survival was 8 months from start of therapy and 23 months from diagnosis.
These results were obtained in a small series of selected patients and require further confirmation in the front-line management of the disease.
Hepatic metastases are often present at diagnosis of carcinoma of unknown primary site (CUP). The objective of this study was to describe the diagnostic and therapeutic strategies used.
One hundred ...and eighteen patients were treated at the Cancer Center of Montpellier from 1993 to 2002 for CUP initially metastatic to the liver. Initial chararcteristics, diagnostic tests, chemotherapies and outcome were retrospectively recorded.
The most frequent histological types observed were adenocarcinoma, undifferentiated, neuroendocrine and squamous-cell carcinomas. Hepatic metastases revealed the cancer in 66 patients and were isolated in 32 patients. Other metastatic sites involved lymph nodes, lung and bone. Pretreatment computed tomography scans of the chest, abdomen and pelvis evaluation were available for more than 80% of patients. Colonoscopy, gastroscopy and bronchoscopy were performed in 58, 56 and 26% of patients respectively. One hundred and seven patients had received at least a front-line of chemotherapy. Seventy-four patients had received platin salt-based chemotherapy, 67 in front-line treatment and 10 in second line. In first-line chemotherapy, overall response rates with or without platin were 19.4 and 20% respectively. One hundred and two of 111 deaths were due to disease progress and seven toxic-related deaths occurred. The median survival was 6.6 months, and 7.8 and 4.6 months in the with or without platin groups respectively (P = 0,35). The median survival for treated patients was 7 months. Multivariate analysis identified two prognostic factors: serum lactodehydrogenase level and performance status.
According to this study, pretreatment evaluations, which were very extensive in some patients, were insufficient to identify the primary site of liver metastases. Because of the poor prognostic, chemotherapy, in absence of clinically demonstrated benefit, has to be reserved for patients with better prognosis. Prospective trials are needed to determine whether use or not of cisplatin should be proposed for standard protocols.
Les métastases hépatiques sont fréquemment présentes lors d’un diagnostic de carcinome de primitif inconnu (CAPI). La prise en charge diagnostique et thérapeutique de ces malades au pronostic sombre est rapportée dans cette étude.
Cent dix-huit malades ont été traités au Centre Régional de Lutte contre le Cancer de Montpellier de 1993 à 2002 pour un CAPI avec métastases hépatiques initiales. Leurs caractéristiques, les examens préthérapeutiques réalisés, les chimiothérapies reçues et l’évolution ont été analysés de façon rétrospective.
Les types histologiques les plus fréquemment retrouvés étaient l’adénocarcinome, les carcinomes indifférenciés, endocrines et épidermoïdes. Dans 66 cas, les lésions hépatiques étaient révélatrices; et chez 32 malades, elles restaient isolées. Les autres sites retrouvés étaient les adénopathies, le poumon, et l’os. Lors du diagnostic, plus de 80 % des malades ont bénéficié d’un scanner thoracoabdominopelvien. Les coloscopies, gastroscopies et bronchoscopies ont été réalisées dans respectivement 58, 56 et 26 % des cas. Cent-sept patients ont reçu au moins une ligne de chimiothérapie. Les sels de platine ont été administrés chez 74 patients dont 67 en première ligne et 10 en seconde ligne. En première ligne, les taux de réponse objective après chimiothérapie avec et sans platine étaient respectivement de 19,4 et 20 %. Cent-deux des 111 décès sont imputables à la progression tumorale et sept aux chimiothérapies. La médiane de survie globale était de 6,6 mois, sans différence significative entre les groupes avec et sans sel de platine (7,8 et 4,6 mois P = 0,35). En analyse multifactorielle, deux variables indépendantes de mauvais pronostic sont retrouvées: l’élévation des lacto-déhydrogénases sériques et l’altération de l’état général. La survie des malades ayant reçu une chimiothérapie était de 7 mois.
Cette étude montre que des explorations parfois extensives n’ont pas permis de retrouver le site primitif des métastases hépatiques. La chimiothérapie, dont l’impact sur la survie n’est pas démontré, doit être réservée aux malades de meilleur pronostic. L’inclusion dans des essais thérapeutiques prospectifs doit être encouragée afin de déterminer la place notamment des sels de platine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
10.
The clinical role of the TME in solid cancer Giraldo, Nicolas A; Sanchez-Salas, Rafael; Peske, J David ...
British journal of cancer,
01/2019, Volume:
120, Issue:
1
Journal Article
Peer reviewed
Open access
The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of ...immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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