AGO‐OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front‐line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib ...demonstrated significantly improved progression‐free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval CI 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh‐risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.
What's new?
Primary results from the randomised phase III AGO‐OVAR 12 trial comparing nintedanib (a triple angiokinase inhibitor) with placebo given in combination with chemotherapy and then continued as maintenance therapy in patients with newly diagnosed advanced ovarian carcinoma demonstrated a significant improvement in progression‐free survival with nintedanib. However, as reported in this paper, final overall survival (OS) results showed that the addition of nintedanib had no impact on OS. These results do not, therefore, support use of nintedanib in ovarian cancer.
Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised ...controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.
These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen PSA concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.
Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable NE–NE) than in the control groups (not reached, 97–NE; hazard ratio HR 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached IQR NE–NE in the combination-therapy groups vs not reached 103–NE in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached NE–NE vs not reached NE–NE; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached NE–NE vs 86 months 83–NE; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached NE–NE vs not reached 103–NE; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).
Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients ...with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer.
The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1Figure: see text and detailed herein.
The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles.
This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.
Background
Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard ...treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective.
Objectives
To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV).
Search methods
We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials.
Selection criteria
Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer.
Data collection and analysis
Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random‐effects model in Review Manager (RevMan) software.
Main results
We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data.
Overall survival (OS) and progression‐free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment‐related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00).
There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD.
We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison.
Authors' conclusions
There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long‐term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.
Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study ...was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy.
HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline–taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety.
A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89–1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74–1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22–0.50, P < 0.0001).
This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.
EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
Summary Background Before this study started, the standard postoperative chemotherapy regimen for stage II–III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, ...avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II–III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. Methods For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II–III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m2 at weeks 1–8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m2 given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. Findings Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8–79·8). 2 year event-free survival was 92·6% (95% CI 89·6–95·7) for treatment including doxorubicin and 88·2% (84·5–92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4–9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3–98·8) for treatment including doxorubicin and 95·8% (93·3–98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. Interpretation Doxorubicin does not need to be included in treatment of stage II–III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. Funding See Acknowledgments for funders.
To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on ...Lung Cancer was held on 11–12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.
Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might ...benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients.
MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat.
The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group.
Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high‐risk cutaneous melanoma. However, the survival advantage associated with this treatment is ...unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists.
Objectives
To assess the disease‐free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high‐risk cutaneous melanoma.
Search methods
We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials.
Selection criteria
We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high‐risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II).
Data collection and analysis
Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan‐Meier plots and then entered into RevMan. Based on the presence of between‐study heterogeneity, we applied a fixed‐effect or random‐effects model for calculating the pooled estimates of treatment efficacy.
Main results
Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta‐analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease‐free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease‐free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between‐study heterogeneity (disease‐free survival: I² statistic = 16%, Q‐test P value = 0.27; overall survival: I² statistic = 6%; Q‐test P value = 0.38).
Considering that the 5‐year overall survival rate for TNM stage II–III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.
Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no‐one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation.
Authors' conclusions
The results of this meta‐analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high‐risk (AJCC TNM stage II‐III) cutaneous melanoma in terms of both disease‐free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.
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