| 51. |
- Merseburger, Axel S., et al.
(författare)
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Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE) : an international, randomised, phase 3b study
- 2022
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 23:11, s. 1398-1408
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough androgen deprivation therapy is typically given long-term for men with metastatic prostate cancer, second-generation hormone therapies are generally discontinued before the subsequent line of treatment. We aimed to evaluate the efficacy of continuing enzalutamide after progression in controlling metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel and prednisolone.MethodsPRESIDE was a two-period, multinational, double-blind, randomised, placebo-controlled, phase 3b study done at 123 sites in Europe (in Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, Turkey, and the UK). Patients were eligible for period 1 (P1) of the study if they had histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, serum testosterone concentrations of 1·73 nmol/L or less, and had progressed during androgen deprivation therapy with a luteinising hormone-releasing hormone agonist or antagonist or after bilateral orchiectomy. In P1, patients received open-label enzalutamide 160 mg per day orally. At week 13, patients were assessed for either radiographic or prostate-specific antigen (PSA) progression (25% or more increase and 2 ng/mL or more above nadir). Patients who showed any decline in PSA at week 13 and subsequently progressed (radiographic progression, PSA progression, or both) were screened and enrolled in period 2 (P2), during which eligible patients were treated with up to ten cycles of intravenous docetaxel 75 mg/m2 every 3 weeks and oral prednisolone 10 mg/day, and randomly assigned (1:1) to oral enzalutamide 160 mg/day or oral placebo. Patients were stratified by type of disease progression. The block size was four and the overall number of blocks was 400. Patients, investigators, and study organisers were masked to treatment assignment. The primary endpoint was progression-free survival analysed in all patients in P2. This trial is registered with ClinicalTrials.gov, NCT02288247, and is no longer recruiting.FindingsBetween Dec 1, 2014, and Feb 15, 2016, 816 patients were screened for P1 of the study. 688 patients were enrolled in P1 and 687 received open-label enzalutamide. In P2, 271 patients were randomly assigned at 73 sites to receive enzalutamide (n=136) or placebo (n=135). The data cutoff for analysis was April 30, 2020. Median progression-free survival with enzalutamide was 9·5 months (95% CI 8·3–10·9) versus 8·3 months (6·3–8·7) with placebo (hazard ratio 0·72 [95% CI 0·53–0·96]; p=0·027). The most common grade 3 treatment-emergent adverse events were neutropenia (17 [13%] of 136 patients in the enzalutamide group vs 12 [9%] of 135 patients in the placebo group) and asthenia (ten [7%] vs six [4%]). The most common grade 4 treatment-emergent adverse event in P2 was neutropenia (23 [17%] of 136 patients in the enzalutamide group vs 28 [21%] of 135 patients in the placebo group). Serious treatment-emergent adverse events were reported in 67 (49%) of 136 patients in the enzalutamide group and 52 (39%) of 135 patients in the placebo group. Two (15%) of 13 deaths in the enzalutamide group (caused by septic shock and haematuria) and one (14%) of seven deaths in the placebo group (caused by actue kidney injury) were associated with docetaxel.InterpretationPRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone.
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| 52. |
- Mirza, Mansoor Raza, et al.
(författare)
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Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial
- 2019
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 20:10, s. 1409-1419
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Tidskriftsartikel (refereegranskat)abstract
- Background Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. Methods This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but amp;lt;= 1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov , number NCT02354131. Findings Between May 23,2016, and March 6,2017,97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16.9 months (IQR 15.4-20.9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11.9 months [95% CI 8.5-16.7] vs 5.5 months [3.8-6.3], respectively; adjusted hazard ratio [HR] 0.35 [95% CI 0.21-0.57], pamp;lt;0.0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27[56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. Interpretation The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
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| 53. |
- Modlin, Irvin M., et al.
(författare)
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Gastroenteropancreatic neuroendocrine tumours
- 2008
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 9:1, s. 61-72
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Forskningsöversikt (refereegranskat)abstract
- Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.
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| 54. |
- Nesti, Cedric, et al.
(författare)
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Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size : a retrospective, Europe-wide, pooled cohort study
- 2023
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 24:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAwareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy.MethodsIn this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693.Findings282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71).InterpretationThis study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.
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| 55. |
- Nordlinger, Bernard, et al.
(författare)
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Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983) : long-term results of a randomised, controlled, phase 3 trial
- 2013
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 14:12, s. 1208-1215
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Tidskriftsartikel (refereegranskat)abstract
- Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m2 (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8.5 years (IQR 7.6-9.5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0.88, 95% CI 0.68-1.14; p=0.34). In all randomly assigned patients, median overall survival was 61.3 months (95% CI 51.0-83.4) in the perioperative chemotherapy group and 54.3 months (41.9-79.4) in the surgery alone group. 5-year overall survival was 51.2% (95% CI 43.6-58.3) in the perioperative chemotherapy group versus 47.8% (40.3-55.0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.
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| 56. |
- Oscarsson, Nicklas, 1974, et al.
(författare)
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Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2–3 trial
- 2019
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 20:11, s. 1602-1614
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier Ltd Background: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. Methods: We did a randomised, controlled, phase 2–3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen—A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18–80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30–40 sessions, 100% oxygen, breathed at a pressure of 240–250 kPa, for 80–90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6–8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. Findings: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210–262) in the hyperbaric oxygen therapy group and 217 days (195–237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2–18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1–2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. Interpretation: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. Funding: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.
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| 57. |
- Pace, Andrea, et al.
(författare)
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European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma
- 2017
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 18:6, s. E330-E340
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Forskningsöversikt (refereegranskat)abstract
- Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.
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| 58. |
- Pasquier, David, et al.
(författare)
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Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups
- 2023
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 24:8, s. e331-e343
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Forskningsöversikt (refereegranskat)abstract
- Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.
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| 59. |
- Petit, Claire, et al.
(författare)
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Chemotherapy and radiotherapy in locally advanced head and neck cancer : an individual patient data network meta-analysis
- 2021
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 22:5, s. 727-736
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%).INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
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