Mental Health Outcomes Among British Healthcare Workers-Lessons From the First Wave of the Covid-19 Pandemic.

OBJECTIVE: To ascertain the level of psychological distress, using validated psychology tools, among British National healthcare workers (HCW) during the first wave of the Covid-19 crisis. METHODS: A multi-centre, anonymized, all-comer staff survey across 3 hospitals in Lancashire, England during the Covid-19 first wave (April to June 2020), consisting of Patient Health Questionnaire (PHQ-9), Perceived Stress Scale-10 (PSS-10), Generalized Anxiety Disorder-7 (GAD-7), and Impact of Events Scale (IES-6). RESULTS: Among 1113 HCW, median (IQR) PHQ-9, GAD-7, PSS-10, and IES-6 score was 7 (3 to 11), 6 (3 to 11), 19 (13 to 24), and 9 (5 to 14), respectively. Potential predictors of higher levels of psychological distress included living alone, disabled dependents, history of depression/anxiety, and being female. CONCLUSIONS: The study indicates a high prevalence of psychological distress during the acute Covid-19 period among HCW, identifies groups at risk and areas of future research.

The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial.

INTRODUCTION: In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS: Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ² analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS: The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS: The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts.

First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.

Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer.

BACKGROUND: Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I-II non-small cell lung cancer. AIM: To determine whether low dose gemcitabine increased event-free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. METHODS: Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) weekly gemcitabine. RESULTS: Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49-88)years and 67 (63%) were male. 86 (81%) were PS 0-1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p=0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild. CONCLUSION: No evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low.

Use of an ATP-based chemosensitivity assay to design new combinations of high-concentration doxorubicin with other drugs for recurrent ovarian cancer.

Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.