The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided ...oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non–small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.
Background
Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. This is an update of a ...Cochrane review first published in 2001 and previously updated in 2006.
Objectives
The two objectives of this review were:
1. To assess the effects of different palliative radiotherapy regimens on improving thoracic symptoms in patients with locally advanced or metastatic non‐small cell lung cancer who are not suitable for radical RT given with curative intent.
2. To assess the effects of radiotherapy dose on overall survival in patients with locally advanced or metastatic non‐small cell lung cancer who are not suitable for radical RT given with curative intent.
Search methods
The electronic databases MEDLINE (1966 ‐ Jan 2014), EMBASE and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished.
Two authors (FM and RS) independently identified all studies that may be suitable for inclusion in the review.
We updated the search up to January 2014.
Selection criteria
Randomised controlled clinical trials comparing different regimens of palliative thoracic radiotherapy in patients with non‐small cell lung cancer.
Data collection and analysis
The reviewers assessed search results independently and possible studies were highlighted and the full text obtained. Data were extracted and attempts were made to contact the original authors for missing information.
The primary outcome measure was improvement in major thoracic symptoms (degree and duration). Secondary outcome measures were short and long term toxicities, effect on quality of life and overall survival.
Patient reported outcomes were reported descriptively. Quantitative data such as survival and toxicity were analysed as dichotomous variables and reported using relative risks (RR).
For this update of the review a meta‐analysis of the survival data was carried out.
Main results
Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update.
There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens.
Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop‐outs were accounted for in all but one study.
All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta‐analysis should be treated with caution.
Meta‐analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence.
The meta‐analysis showed no significant difference in 1‐year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta‐analysis of 1‐year overall survival for patients with good performance status (WHO performance status 0‐1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1‐year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence).
Authors' conclusions
Radiotherapy for patients with incurable non‐small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.
No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to ...assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.
This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.
Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio HR 0·67 95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 95% CI 0·52–0·91; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six 3% of 221 in the nivolumab group vs two 2% of 111 in the placebo group) and infusion-related reaction (six 3% vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.
Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb.
IMPORTANCE: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard ...radiotherapy regimen. OBJECTIVE: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. INTERVENTIONS: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). MAIN OUTCOMES AND MEASURES: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was −11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. RESULTS: Among 686 randomized patients (median interquartile range age, 70 64-77 years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, −3.5% 1-sided 95% CI, −11.5% to ∞; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was −0.4% (63.9% vs 64.3%; 1-sided 95% CI, −6.9 to ∞; P value for noninferiority = .004) at week 1, −0.7% (66.8% vs 67.6%; 1-sided 95% CI, −8.1 to ∞; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; 1-sided 95% CI, −4.6 to ∞; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 95% CI, 0.74-1.41). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. CONCLUSIONS AND RELEVANCE: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. TRIAL REGISTRATION: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008
Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was ...to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.
Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response ...and survival in muscle-invasive bladder cancer.
NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment.
Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0–44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio OR 1·25, 70% CI 0·84–1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74–3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 30% of 57 patients in the nintedanib group vs 13 21% of 63 patients in the placebo group OR 1·63, 95% CI 0·71–3·76; p=0·29) and decreased neutrophil count (22 39% in the nintedanib group vs seven 11% in the placebo group 5·03, 1·95–13·00; p=0·0006). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction.
The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer.
Boehringer Ingelheim.
Non–small-cell lung cancer (NSCLC) has a significant impact on patients’ health-related quality of life (HRQOL). This study aimed to measure health state utility values representing the individual’s ...preferences for specific health-related outcomes in advanced NSCLC patients and to assess predictive parameters.
We conducted a prospective quality-of-life survey on advanced NSCLC patients in 25 hospitals in Europe, Canada, Australia, and Turkey. HRQOL was assessed using the EuroQol (EQ-5D) questionnaire and EQ-5D utility and EQ-visual analog (EQ-VAS) scores were estimated.
Three hundred nineteen patients were recruited of which 263 had evaluable data. Mean utility for progression-free (PF) patients on first-, second-, and third-/fourth-line treatment was 0.71 (SD = 0.24), 0.74 (SD = 0.18), and 0.62 (SD = 0.29), respectively. Mean utility for patients with progressive disease (PD) while on first-, second- and third-/fourth-line treatment was 0.67 (SD = 0.2), 0.59 (SD = 0.34), and 0.46 (SD = 0.38), respectively. Overall, patients with PD had lower mean utility scores than PF patients (0.58 versus 0.70). The results of the EQ-VAS showed that the score decreased with later treatment lines. Patients with PD had a 10-point decrease in VAS scores compared with PF patients (53.7 versus 66.6). The regression analysis revealed that stage IV disease, higher lines of treatment, and health state were significant predictors of utility at the 10% level.
The results presented indicate a substantial impact of lung cancer on patients’ HRQOL, with stage IV disease, line of treatment, and PD, resulting in considerable deterioration of utility. The values obtained here will inform evaluations of cost-utility for NSCLC therapies.
•A prognostic model for recovery of mobility and survival in metastatic spinal cord compression.•Recovery of mobility is greatest in those ambulant with primary breast or prostate cancer.•Survival is ...greatest in ambulant females with breast cancer, and no extraskeletal metastases.
Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival.
SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348).
The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1–T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p < 0.05). The ROC AUC for the selected model was 75% (95%CI: 69–81) in the SCORAD validation set and 68% (95%CI: 62–74) in the external validation registry data.
The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p < 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6–82.0) in the validation set.
Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.
Abstract Background and purpose A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks ...(55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule. Materials and methods 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed. Results 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0 months and 2 year overall survival was 50%. Conclusion These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime.
CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and ...immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE- or blood-derived CD14
+
cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14
+
cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14
+
cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14
+
cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E
2
(PGE
2
)) and adenosine. Inhibition of PGE
2
receptors or adenosine A
2
receptors blocked CD73-induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14
+
cells. TNFα production by CD73
+
CD14
+
cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE
2
, cAMP or adenosine on human CD14
+
cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.
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