Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer.

OBJECTIVES: Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer. METHODS: All new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021. RESULTS: From July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046). CONCLUSIONS: Early prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.

Biomarkers of systemic inflammation provide additional prognostic stratification in cancers of unknown primary.

BACKGROUND: Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. PATIENTS AND METHODS: CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. RESULTS: Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable-risk cCUP. On multivariate analysis c-reactive protein (CRP) (p < 0.001) and the Scottish Inflammatory Prognostic Score (SIPS: combining albumin and neutrophil count) (p < 0.001) were independently predictive of survival. CRP and SIPS effectively stratified survival in patients with both favourable-risk and poor-risk cCUP based on clinicopathological features. CONCLUSIONS: Biomarkers of systemic inflammation are reliable prognostic factors in patients with cCUP, regardless of clinicopathological subgroup. We recommend that CRP or SIPS are incorporated into routine clinical assessments of patients with cCUP as a tool to aid investigation and/or treatment decision-making across all groups. Established clinicopathological factors can then be used to inform management pathways and specific systemic anticancer therapy selection.

Prognostic value of the Scottish Inflammatory prognostic Score in patients with NSCLC expressing PD-L1 ≥ 50 % progressing on first-line pembrolizumab.

BACKGROUND: Most patients with advanced non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab monotherapy will experience progressive disease (PD). Only a minority will go on to receive subsequent systemic anticancer therapy for which outcomes are guarded. We investigated the prognostic significance of biomarkers of systemic inflammation following failure of first-line pembrolizumab for NSCLC to aid subsequent management decisions. METHODS: Patients with radiological and/or clinical evidence of PD on first-line pembrolizumab for advanced NSCLC at a regional Scottish cancer centre were identified. Inflammatory biomarkers at the time of PD, including serum albumin, neutrophil count and the Scottish Inflammatory Prognostic Score (SIPS; combing albumin and neutrophils), and clinicopathological factors, including age, sex, histology, PDL1 expression and time to PD were recorded. The relationship between these and post-progression overall survival (ppOS) were examined. RESULTS: Data were available for 211 patients. Median ppOS was 2.1 months. Only SIPS was predictive of ppOS on multivariate analysis (HR2.54 (95 %CI 1.81-3.56) (<0.001)), stratifying ppOS from 0.8 months (SIPS2), to 1.8 months (SIPS1), to 8.1 months (SIPS0) (p < 0.001). Thirty (14 %) patients received second-line systemic anticancer therapy with median ppOS 8.7 months. These patients had lower levels of systemic inflammation, as defined by albumin (p < 0.001), neutrophil count (p = 0.002), and SIPS (p = 0.004)), than all other patients. CONCLUSIONS: SIPS, a simple biomarker of systemic inflammation, predicts ppOS after first-line pembrolizumab and may be useful alongside routine assessments of patient fitness to inform individualised discussions about subsequent treatment. We highlight poor outcomes in this patient group and a role for SIPS in signposting transition to best supportive care and early referral to palliative care. It may also help identify a small group of patients most likely to benefit from further lines of therapy.

Early prehabilitation in suspected locally advanced and metastatic lung cancer.

OBJECTIVES: The most common treatment for locally advanced and metastatic lung cancer is best supportive care. Patients with lung cancer are often comorbid with a high symptom burden. We wanted to assess whether early prehabilitation was feasible in patients with likely lung cancer. METHODS: Patients were offered prehabilitation if they were attending the new patient respiratory clinic, had a CT scan suggesting stage III or IV lung cancer and undergoing further investigations. Patients receiving palliative care were ineligible. All prehabilitation patients were referred to a palliative medicine physician, registered dietitian and rehabilitation physiotherapist. RESULTS: 50 patients underwent prehabilitation between June 2021 and August 2022. The median age was 72 years (range 54-89 years). 48 patients had lung cancer. 84% of patients attended all three interventions.Half of the palliative care consultations focused on pain. Half of the patients seen had a change in medication. 25% of patients' weights were stable, 32% required a food-first strategy and 33% required oral nutritional supplements. 57% of patients discussed managing breathlessness with the physiotherapist. CONCLUSIONS: Early prehabilitation is feasible alongside the investigation of locally advanced and metastatic lung cancer. Further work will aim to assess its impact on admission to the hospital, survival and treatment rates.

Immune-Related Adverse Events, Biomarkers of Systemic Inflammation, and Survival Outcomes in Patients Receiving Pembrolizumab for Non-Small-Cell Lung Cancer.

BACKGROUND: Pembrolizumab monotherapy for non-small-cell lung cancer (NSCLC) expressing PD-L1 ≥ 50% doubles five-year survival rates compared to chemotherapy. However, immune-related adverse events (irAEs) can cause severe, long-term toxicity necessitating high-dose steroids and/or treatment cessation. Interestingly, patients experiencing irAEs demonstrate better survival outcomes. Biomarkers of systemic inflammation, including the Scottish Inflammatory Prognostic Score (SIPS), also predict survival in this patient group. This study examines the relationship between inflammatory status, irAEs, and survival outcomes in NSCLC. METHODS: A retrospective analysis was conducted on patients with NSCLC expressing PD-L1 ≥ 50% receiving first-line pembrolizumab monotherapy at a large cancer centre in Scotland. Regression analyses were conducted to examine the relationship between SIPS, irAEs, and survival. RESULTS: 83/262 eligible patients (32%) experienced an irAE. Dermatological, endocrine, gastrointestinal, and hepatic, but not pulmonary, irAEs were associated with prolonged PFS and OS (p <= 0.011). Mild irAEs were associated with better PFS and OS in all patients, including on time-dependent analyses (HR0.61 [95% CI 0.41-0.90], p = 0.014 and HR0.41 [95% CI 0.26-0.63], p < 0.001, respectively). SIPS predicted PFS (HR 1.60 [95% CI 1.34-1.90], p < 0.001) and OS (HR 1.69 [95% CI 1.41-2.02], p < 0.001). SIPS predicted the occurrence of any irAE in all patients (p = 0.011), but not on 24-week landmark analyses (p = 0.174). The occurrence of irAEs predicted favourable outcomes regardless of the baseline inflammatory status (p = 0.015). CONCLUSION: The occurrence of certain irAEs is associated with a survival benefit in patients with NSCLC expressing PD-L1 ≥ 50% receiving pembrolizumab. We find that the association between low levels of systemic inflammation and the risk of irAEs is confounded by their independent prognostic value.

Real-World Impact of SABR on Stage I Non-Small-Cell Lung Cancer Outcomes at a Scottish Cancer Centre.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) offers patients with stage I non-small-cell lung cancer (NSCLC) a safe, effective radical therapy option. The impact of introducing SABR at a Scottish regional cancer centre was studied. METHODS: The Edinburgh Cancer Centre Lung Cancer Database was assessed. Treatment patterns and outcomes were compared across treatment groups (no radical therapy (NRT), conventional radical radiotherapy (CRRT), SABR and surgery) and across three time periods reflecting the availability of SABR (A, January 2012/2013 (pre-SABR); B, 2014/2016 (introduction of SABR); C, 2017/2019, (SABR established)). RESULTS: 1143 patients with stage I NSCLC were identified. Treatment was NRT in 361 (32%), CRRT in 182 (16%), SABR in 132 (12%) and surgery in 468 (41%) patients. Age, performance status, and comorbidities correlated with treatment choice. The median survival increased from 32.5 months in time period A to 38.8 months in period B to 48.8 months in time period C. The greatest improvement in survival was seen in patients treated with surgery between time periods A and C (HR 0.69 (95% CI 0.56-0.86), p < 0.001). The proportion of patients receiving a radical therapy rose between time periods A and C in younger (age ≤ 65, 65-74 and 75-84 years), fitter (PS 0 and 1), and less comorbid patients (CCI 0 and 1-2), but fell in other patient groups. CONCLUSIONS: The introduction and establishment of SABR for stage I NSCLC has improved survival outcomes in Southeast Scotland. Increasing SABR utilisation appears to have enhanced the selection of surgical patients and increased the proportion of patients receiving a radical therapy.

Hypoalbuminaemia as a Prognostic Biomarker of First-Line Treatment Resistance in Metastatic Non-small Cell Lung Cancer.

Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC. Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined. Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23-2.7) (p =0.003) and HR2.55 (95%CI 1.78-3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20-41.72, p = 0.003) and RR3.60 (95%CI 1.74-6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86-4.46) (p < 0.001) and HR2.67 (95%CI 1.74-4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61-3.82) (p < 0.001) and HR2.87 (95%CI 1.91-4.31) (p < 0.001) respectively). Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.

Characterisation and outcomes of patients referred to a regional cancer of unknown primary team: a 10-year analysis.

BACKGROUND: In the United Kingdom, national guidance published in 2010 recommended the establishment of specialist teams to improve clinical pathways for patients presenting with malignancies of undefined primary origin (MUO) and cancer of unknown primary (CUP). This study sought to define outcomes of patients referred to a regional MUO/CUP service. METHODS: Data were collected prospectively on all patients (n = 1225) referred to a regional CUP team over a 10-year period. Patient demographics, clinical, pathological and outcome data were recorded and analysed. RESULTS: Confirmed CUP (cCUP) was diagnosed in 25% of patients. A primary metastatic cancer was identified in 36%, 5% were diagnosed with provisional CUP (pCUP), 27% retained the diagnosis of MUO and in 8% a non-cancer diagnosis was made. Median survival was low in all patients with a final malignant diagnosis: primary identified 9.0 months, cCUP 4.0 months, pCUP 1.5 months and MUO 1.5 months. CONCLUSIONS: Patients presenting with MUO have poor outcomes irrespective of the final diagnosis. These patients need a patient-centred, streamlined, rapid diagnostic pathway. There are clear benefits to primary and secondary care teams having access to a dedicated, multidisciplinary MUO/CUP service, with clinical nurse specialists supporting the patients, to help facilitate this pathway and ensure early oncology review.

Challenging presentations of germ cell tumours in routine clinical practice.

Testicular cancer is the most common malignancy in young men. We discuss four cases of germ cell tumours (GCTs) presenting to general practitioners and physicians where there were notable preventable delays in the diagnosis and management. This diagnostic delay is associated with a more advanced stage of disease, and subsequent increased treatment-related morbidity and decreased survival. Our series highlights the variety of ways in which GCTs may present and we discuss the importance of prompt diagnosis through a thorough history and examination, early measurement of serum tumour markers and appropriate multidisciplinary team discussion. GCTs are highly curable cancers in the majority of patients and delays in management can, therefore, have devastating consequences.

Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial.

BACKGROUND: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0-1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear. We aimed to evaluate the safety and efficacy of pembrolizumab in these patients. METHODS: We did a multicentre, single-arm, open-label, phase 2 trial (PePS2) in ten hospitals in the UK, in which patients with NSCLC and a rigorous ascription of PS2 were given pembrolizumab 200 mg every 3 weeks. No masking was used in this trial. We stratified the treatment evaluation by tumour proportion score (TPS) and line of therapy. Co-primary outcomes were: (1) durable clinical benefit (DCB), defined as the occurrence of complete response, partial response, or stable disease that continues until at least the second CT scan scheduled at 18 weeks; and (2) toxicity, defined as the occurrence at any time of treatment-related dose delay or treatment discontinuation due to an adverse event. Analysis included all patients who received any pembrolizumab. As well as reporting simple observed incidence for the co-primary outcomes, DCB and toxicity, we also estimated incidence using a model-based method for correlated binary outcomes. This study is registered with ClinicalTrials.gov, NCT02733159; EudraCT, 2015-002241-55; and ISRCTN, 10047797. FINDINGS: Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65-75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for DCB was 38% (95% CI 21-57) in first-line patients (n=24) and 36% (22-52) in subsequent-line patients (n=36); DCB was 22% (11-41) in patients with a TPS less than 1% (n=27), 47% (25-70) in patients with a TPS of 1-49% (n=15), and 53% (30-75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3-4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each). INTERPRETATION: Patients with NSCLC of PS2 are a group of patients of unmet therapeutic need. The PePS2 trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with PS0-1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2. FUNDING: Merck, Sharp & Dohme.