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•DAAs improve survival in patients with HCV-related early HCC that has been successfully treated.•The improvement in survival seems to be caused by a reduction in hepatic ...decompensation.•DAAs did not impact on HCC recurrence.
The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation.
We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared.
In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio HR 0.39; 95% CI0.17–0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR0.70; 95% CI0.44–1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR0.32; 95% CI0.13–0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00–0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11–0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02–0.38; p = 0.02).
In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment.
We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced.
Summary Background High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient ...benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. Methods We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1–20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8–1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2 ) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration–time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01704716 , and EudraCT, number 2006-001489-17. Findings Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3–9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45–56) versus 38% (32–43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3–4 adverse events were general condition (74 26% of 281 in the busulfan and melphalan group vs 103 38% of 270 in the carboplatin, etoposide, and melphalan group), infection (55 19% of 283 vs 74 27% of 271), and stomatitis (138 49% of 284 vs 162 59% of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1–3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Interpretation Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. Funding European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.
Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 HER2-negative) breast cancer is an aggressive disease with poor ...outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab.
In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup).
Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval CI, 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.
Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).
Objective
We evaluated survival outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for clinical T2 renal masses (cT2RM) controlling for R.E.N.A.L. nephrometry score.
Patients and ...Methods
A two‐centre study comprised of 202 patients with cT2RM who underwent RN (122) or PN (80) between July 2002 and June 2012 (median follow‐up 41.5 months). Kaplan−Meier analysis compared overall survival (OS), cancer‐specific survival (CSS) and progression‐free survival (PFS) among the entire cohort and within categories of R.E.N.A.L. nephrometry score of ≥10 and <10. Association between procedure and PFS and OS was analysed using Cox‐proportional hazard.
Results
There were no significant differences between PN and RN in clinical T stage and R.E.N.A.L. nephrometry scores. For RN and PN, the 5‐year PFS was 69.8% and 79.9% (P = 0.115), CSS was 82.5% and 86.7% (P = 0.407), and OS was 80% and 83.3% (P = 0.291). Cox regression showed no association between RN vs PN and PFS; a R.E.N.A.L. nephrometry score of ≥10 was associated with a shorter PFS (hazard ratio 6.69, P = 0.002). Kaplan–Meier analysis for RN vs PN showed no difference in PFS for entire cohort or within the R.E.N.A.L. nephrometry score categories of ≥10 and <10. The PFS was better for those with R.E.N.A.L nephrometry scores of <10 vs ≥10 (P < 0.001) and for cT2a vs cT2b tumours (P = 0.012). OS was no different between cT2a and cT2b tumours; patients with R.E.N.A.L. nephrometry scores of ≥10 were more likely to die from disease (P < 0.001) or any cause (P < 0.001) vs those with R.E.N.A.L. nephrometry scores of <10.
Conclusions
PN may be oncologically effective for cT2RM. A R.E.N.A.L nephrometry score of ≥10 is negatively associated with OS among cT2RM compared with a score of <10 and provides additional risk assessment beyond clinical T stage. Further follow‐up and prospective randomised investigation is requisite to confirm efficacy of PN for cT2RM.
Platelets promote tumor growth and metastasis in several tumor types. Recent research has found platelets can extravasate and infiltrate into the tumor stroma and interact with the tumor ...microenvironment. The prognostic role of platelet infiltration in colorectal cancer (CRC) remains controversial. A pan‐cancer survival analysis was performed to find the potential prognostic value of platelet infiltration in patients with cancer. A survival analysis and a nomogram prognostic model were established to further confirm the results with data from our center. The correlations between patient outcomes and tumor‐infiltrating platelets (TIPs) were identified by immunohistochemical staining for CD42b. The prognostic accuracy and discriminative ability of the nomogram were determined by the concordance index (C‐index) and a calibration curve. The pan‐cancer survival analysis showed platelet infiltration can lead to a poor prognosis in patients with several types of cancers, including CRC. Platelet infiltration was associated with overall survival (OS) and disease‐free survival (DFS) in both primary and validation cohorts. The C‐index values of the nomogram for predicting OS and DFS were 0.774 and 0.769, respectively, which were higher than that of the TNM staging system alone. Our study found platelet infiltration has a potential prognostic value regarding postsurgical survival in CRC patients. The proposed nomogram resulted in a more accurate prognostic prediction for postsurgical CRC patients.
What's new?
Recent research has increasingly linked the tumor microenvironment with tumor progression and metastasis. Platelets are known to infiltrate and interact with the tumor microenvironment. In this study, the authors found that platelet infiltration correlated with poor prognosis in several types of cancer. They then validated their analysis in tumors from colorectal cancer (CRC) patients. Platelet infiltration was associated with decreased postsurgical survival, and this measure was more accurate than TMN staging alone. Platelet infiltration might therefore offer a useful prognostic biomarker for postsurgical CRC patients.
Background
To assess whether extending the observation period in patients with a near clinical complete response (near cCR) after chemoradiation (CRT) leads to an impaired oncological outcome.
...Methods
Patients who had a clinical complete response (cCR) 8–10 weeks after CRT restaging with magnetic resonance imaging and endoscopy were offered a watch-and-wait strategy (W&W1), while patients with a near cCR were offered to undergo local excision or a second restaging 6–12 weeks later. Patients who achieved a cCR at the second restaging were also offered a watch-and-wait strategy (W&W2).
Results
Overall, 102 patients with a cCR at the first restaging immediately entered the W&W1, while the remaining 68 patients had a near cCR: 19 patients underwent transanal endoscopic microsurgery and 49 patients opted for a second restaging. Additionally, 44/49 (90%) patients showed a cCR at the second restaging and entered the W&W2. Patients in the W&W1 group had a 2-year local regrowth-free rate (LRFR) of 84% and 2-year overall survival (OS) of 99%, while patients in the W&W2 group had a 2-year LRFR of 73% and OS of 98% (
p
> 0.05). Multivariable Cox regression analyses showed that late inclusion was not a significant predictive factor for higher risk of LR or lower non-regrowth disease-free survival.
Conclusions
Overall, 90% of patients with a near cCR 8–10 weeks after CRT will proceed to a cCR 6–12 weeks later; therefore, it seems logical to extend the observation period rather than to proceed to surgery. Although there is a non-significant increase in local regrowth rate in these patients, it does not seem to impact the oncological outcome.
Cystic fibrosis (CF) is the most common inherited disease in Caucasians, affecting around 10,000 individuals in the UK today. Prognosis has improved considerably over recent decades with ongoing ...improvements in treatment and care. Providing up-to-date survival predictions is important for patients, clinicians and health services planning.
Flexible parametric survival modelling of UK CF Registry data from 2011 to 2015, capturing 602 deaths in 10,428 individuals. Survival curves were estimated from birth; conditional on reaching older ages; and projected under different assumptions concerning future mortality trends, using baseline characteristics of sex, CFTR genotype (zero, one, two copies of F508del) and age at diagnosis.
Male sex was associated with better survival, as was older age at diagnosis, but only in F508del non-homozygotes. Survival did not differ by genotype among individuals diagnosed at birth. Median survival ages at birth in F508del homozygotes were 46years (males) and 41years (females), and similar in non-homozygotes diagnosed at birth. F508del heterozygotes diagnosed aged 5 had median survival ages of 57 (males) and 51 (females). Conditional on survival to 30, median survival age rises to 52 (males) and 49 (females) in homozygotes. Mortality rates decreased annually by 2% during 2006–2015. Future improvements at this rate suggest median survival ages for F508del homozygous babies of 65 (males) and 56 (females).
Over half of babies born today, and of individuals aged 30 and above today, can expect to survive into at least their fifth decade.
Evidence before this study
We searched PubMed with terms “(cystic fibrosis survival) and (projection OR model OR registry OR United Kingdom OR UK)” to identify relevant studies on survival estimates for individuals with cystic fibrosis (CF). We also considered the most recent annual report from the UK Cystic Fibrosis Registry (Cystic Fibrosis Trust, 2016), a review by Buzzetti and colleagues (2009), the chapter on Epidemiology of Cystic Fibrosis by MacNeill (2016), the study of MacKenzie and colleagues (2014), and references therein. There have been many studies of factors associated with survival in CF; most have focused on identifying risk factors, and only a few have presented estimated survival curves, which are the focus of this work. The most recent study of survival in the UK is by Dodge and colleagues (2007), who used data obtained from CF clinics and the national death register, and gave an estimate of survival for babies born in 2003. We found no previous studies that have obtained detailed information on survival using UK Cystic Fibrosis Registry data. Jackson and colleagues obtained survival estimates for the US and Ireland using registry data (Jackson et al., 2011). MacKenzie and colleagues used US Cystic Fibrosis Foundation Patient Registry data from 2000 to 2010 to project survival for children born and diagnosed with CF in 2010, accounting for sex, genotype and age at diagnosis (MacKenzie et al., 2014). Previous studies on estimated survival in CF have become out of date or have not accounted for the full range of patient characteristics available at birth. Few have presented conditional survival estimates (Dodge et al., 2007).
Added value of this study
This is the first study to yield detailed survival statistics using the UK Cystic Fibrosis Registry, which is one of the largest national CF registries outside of the US and has almost complete coverage of the UK CF population. The primary goal was to leverage the long-term follow-up of the nearly complete UK CF population available in the Registry for the purposes of producing accurate, precise predictions in the modern era of CF care. Estimates are presented from birth and conditional on survival to older ages. These are the first conditional estimates in CF to also account for genotype, sex and age at diagnosis, which were each included in the modelling using a flexible approach. Projections are also provided under different scenarios based on downward trends in mortality rates. Our use of flexible parametric survival models is novel in this field, and our approach could be used to provide modern survival statistics for other chronic diseases and disorders.
Implications of all the available evidence
Our estimates of future survival in CF under a range of different scenarios are based on data on nearly all individuals living with the disease in the UK in recent times, reflective of a modern era of care, and are most appropriate for the families of babies being born in the present day with CF. Conditional estimates inform patients who have already reached an older age, and their clinicians. Over half of babies born today, and of individuals aged 30years and above alive today, can expect to survive into their fifth decade. Insights based on our survival projections can be used to inform future needs in CF health care provision.
Summary
Use of surrogate end‐points such as progression‐free survival (PFS) and other time‐to‐event (TTE) end‐points is common in multiple myeloma (MM) clinical trials. This systematic review ...characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end‐points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co‐primary end‐point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval CI 0.38–0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30–0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42–0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.
The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this ...paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions.
This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0–1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1–3 vs 4–5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744.
99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19–54) in the control group versus 26 months (23–37) in the SABR group. Median overall survival was 28 months (95% CI 19–33) in the control group versus 41 months (26–not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30–1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5–34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group.
SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit.
Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.
A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response ...to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
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