Summary Background In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten ...tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. Methods The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02 -positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 μg), with one dose of cyclophosphamide (300 mg/m2 ) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01265901. Findings Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92–35·64). Median overall survival did not differ significantly between the groups (33·17 months 95% CI 27·81–41·36 in the sunitinib plus IMA901 group vs not reached 33·67–not reached in the sunitinib monotherapy group; hazard ratio 1·34 0·96–1·86; p=0·087). 116 (57%) of 202 patients in the sunitinib plus IMA901 group and 62 (47%) of 132 in the sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse possibly related to sunitinib, one oesophageal varices haemorrhage possibly related to sunitinib, one cardiac arrest possibly related to sunitinib, and one myocardial infarction) and eight (6%) patients in the sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident possibly treatment related, and sepsis). Interpretation IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. Funding Immatics Biotechnologies.
Summary Background Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense ...oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. Methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov , number NCT01188187 . The trial is completed and final analyses are reported here. Findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months 95% CI 20·9–24·8 with docetaxel, prednisone, and custirsen vs 22·0 months 19·5–24·0 with docetaxel and prednisone; hazard ratio HR 0·93, 95% CI 0·79–1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 13% vs 28 6%; grade 4, 98 20% vs 77 15%), febrile neutropenia (grade 3, 52 10% vs 31 6%; grade 4, four 1% vs two <1%), and fatigue (grade 3, 53 11% vs 41 8%; grade 4, three 1% vs one <1%). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. Funding OncoGenex Technologies.
Abstract Objective Comorbidity and performance indices (CPIs) are useful tools to evaluate patient׳s risk of comorbidities and thus may guide clinical decision making regarding surgery or multimodal ...therapy approaches. Hence, the aim of the current study was to assess the predictive capacity of CPIs comprising the American Society of Anaesthesiologists (ASA)-score, the Charlson comorbidity index (CCI), the age-adjusted CCI (ACCI), and the Eastern Cooperative Oncology Group performance status (ECOG-PS) in patients with upper tract urothelial carcinoma (UTUC) who were treated with radical nephroureterectomy (RNU). Methods and materials A total of 242 patients with UTUC underwent RNU without neoadjuvant chemotherapy between 1992 and 2012 at 3 German academic centers. Patients were stratified according to the pre-RNU CPIs dichotomized as ASA 1/2 vs.≥3, CCI 0 to 2 vs.>2, ACCI 0 to 5 vs. >5, and ECOG-PS 0 to 1 vs. >1. We assessed the associations of CPIs with clinicopathologic features, as well as the prognostic effect on recurrence-free survival, cancer-specific survival (CSS), overall survival, and cancer-independent mortality (CIM), using univariable and multivariable Cox regression analyses. Results Sixty-two patients (25.6%) had an ASA-score≥3, 71 patients (29.3%) a CCI>2, 50 patients (20.7%) an ACCI>5, and 122 (50.4%) patients an ECOG-PS>1. The ASA-score ( P = 0.001), CCI ( P = 0.029), and the ECOG-PS ( P <0.001) were significantly associated with age. In addition, the ECOG-PS was associated with pelvicalyceal tumors ( P = 0.012), and the CCI with preoperative hydronephrosis ( P = 0.026). The median follow-up was 30 months. In Kaplan-Meier analyses, ACCI>5 ( P ≤0.025) and ECOG-PS>1 ( P ≤0.042) were associated with recurrence-free survival, CSS, and overall survival, and ASA-score≥3 ( P = 0.011) and ACCI>5 ( P = 0.006) with CIM. In multivariable analysis that adjusted for standard clinicopathologic parameters, an ECOG-PS>1 was an independent predictor for CSS (hazard ratio = 1.89, P = 0.019), and an ASA-score≥3 (hazard ratio = 1.86, P = 0.026) was a predictor for CIM. Conclusion CPIs are easy assessable predictors for outcome in patients with UTUC who were treated with RNU. CPIs have carefully to be taken into account in patient counseling regarding operative decision making and multimodal treatment.
Prevention and early detection of prostate cancer Cuzick, Jack, Prof; Thorat, Mangesh A, MBBS; Andriole, Gerald, Prof ...
Lancet oncology/Lancet. Oncology,
10/2014, Letnik:
15, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Summary Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer ...opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.
Zusammenfassung
Die multiparametrische Magnetresonanztomographie (mpMRT) ist fester Bestandteil der Prostatakarzinomdiagnostik. Sie soll gemäß der S3-Leitlinie „Prostatakarzinom“ zur Primärdiagnostik ...sowie in der aktiven Überwachung eingesetzt werden. Die mpMRT beinhaltet hochauflösende T2-gewichtete (T2w) Sequenzen, diffusionsgewichtete („diffusion-weighted imaging“, DWI) und dynamische kontrastmittelgestützte Sequenzen (DCE), welche Grundlage für die Befundung gemäß der PI-RADS(Prostate Imaging Reporting and Data System)-Klassifikation sind.
PDF
