Now showing items 1-20 of 13230

    • Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy

      Elumalai, T.; Croxford, W.; Buijtenhuijs, B.; Conroy, R.; Sanderson, B.; Enting, D.; Aversa, C.; Doss, G.; Das, A.; Vasudev, N. S.; et al. (2022)
      Aims Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. Materials and methods A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. Results The median follow-up was 18.9 (15.8–21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4–10.5) and 4.5 months (3.5–5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. Conclusions Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.
    • Work-Up and Outcome of Hepatic Resection for Peri-Hilar Cholangiocarcinoma (PH-CCA) without Staging Laparoscopy

      Jegatheeswaran, S.; Stathakis, P.; Spiers, H. V. M.; Mohammed, F.; Petras, P.; Satyadas, T.; Parker, M. J.; Lamarca, A.; Jamdar, S.; Sheen, A. J.; et al. (2022)
      Background: This study reports the outcome of a work-up programme for resection of peri-hilar cholangiocarcinoma (PH-CCA) without the use of staging laparoscopy. Methods: This is a clinical case cohort series of patients undergoing surgical resection of PH-CCA without the use of staging laparoscopy in the work-up algorithm. During the 13 years from 1 January 2009 to 1 January 2022, 32 patients underwent laparotomy for planned surgical resection of PH-CCA. Data were collected on demographic profile, admission biochemistry, radiology, pre-operative intervention, operation and outcome, together with post-operative complications and disease-free and overall survival. Results: All patients underwent pre-operative contrast-enhanced CT. Twenty-four (75%) underwent pre-operative MR. Twenty-three (72%) underwent pre-operative biliary drainage. Twenty-nine patients (91%) had either type III or IV peri-hilar cholangiocarcinoma. One patient (3%) in this series underwent a non-resectional laparotomy. Twenty-nine (91%) had a final histopathological diagnosis of PH-CCA. One further patient had a final diagnosis of an intraductal papillary neoplasm of the biliary tree (IPNB) with high-grade dysplasia but no invasive cancer. Eleven patients (36%) received chemotherapy after surgery. The median (95% CI) time to recurrence was 14 (7–31) months. The median survival was 25 (18-upper limit not reached) months. Conclusion: This cohort of 32 patients undergoing attempted resection for PH-CCA without the use of staging laparoscopy in the work-up algorithm indicates that with careful attention to patient fitness and cross-sectional and interventional radiologic/endoscopic imaging, a very low non-therapeutic laparotomy rate of 3% can be achieved and sustained.
    • ADAURA: The Splash of Osimertinib in Adjuvant EGFR-Mutant Non-small Cell Lung Cancer

      Ortega-Franco, A.; Rafee, S. (2022)
      The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB–IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib’s fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.
    • Cemiplimab in advanced cutaneous squamous cell carcinoma: the UK experience from the Named Patient Scheme

      Challapalli, A.; Watkins, S.; Cogill, G.; Stewart, G.; Ellis, S.; Sykes, A.; Nobes, J.; Yip, K.; Barthakur, U.; Board, R.; et al. (2022)
    • In Reply to Anto et al

      Yeates, P.; Fuller, R.; McKinley, R. K. B. (2022)
    • Translation of Prognostic and Pharmacodynamic Biomarkers from Trial to Non-trial Patients with Metastatic Castration-resistant Prostate Cancer Treated with Docetaxel

      Elumalai, T.; Barker, C.; Elliott, T.; Malik, J.; Tran, A.; Hudson, A.; Song, Y. P.; Patel, K.; Lyons, J.; Hoskin, P.; et al. (2022)
      Aims We conducted a pooled analysis of four randomised controlled trials and a non-trial retrospective dataset to study the changes in serum prostate-specific antigen (PSA) concentrations during treatment and its impact on survival in men treated with docetaxel for metastatic castration-resistant prostate cancer. We also compared the outcomes and pre-treatment prognostic factors between trial and non-trial patients. Materials and methods Data were obtained from four randomised controlled trials and a non-trial cohort from a tertiary cancer centre. The PSA kinetics covariates chosen were absolute value (PSAT), best percentage change (BPCH) and tumour growth rate (K). The association between the covariates collected and overall survival was assessed within a Cox proportional hazards model. How well a covariate captured the difference between trial and non-trial patients was assessed by reporting on models with or without trial status as a covariate. Results We reviewed individual datasets of 2282 patients. The median overall survival for trial patients was 20.4 (95% confidence interval 19.6–22.2) months and for the non-trial cohort was 12.4 (10.7–14.7) months (P < 0.001). Of the pre-treatment factors, we found that only lactate dehydrogenase fully captured the difference in prognosis between the trial and non-trial cohorts. All PSA kinetic metrics appeared to be prognostic in both the trial and non-trial patients. However, the effect size was reduced in non-trial versus trial patients (interaction P < 0.001). Of the time-dependent covariates, we found that BPCH best captured the difference between trial and non-trial patient prognosis. Conclusions The analysis presented here highlights how data from open-source trial databases can be combined with emerging clinical practice databases to assess differences between trial versus non-trial patients for particular treatments. These results highlight the importance of developing prognostic models using both pre-treatment and time-dependent biomarkers of new treatments.
    • Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer

      Nalio Ramos, R.; Missolo-Koussou, Y.; Gerber-Ferder, Y.; Bromley, C. P.; Bugatti, M.; Núñez, N. G.; Tosello Boari, J.; Richer, W.; Menger, L.; Denizeau, J.; et al. (2022)
      Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
    • Understanding the Differences Between Bayesian and Frequentist Statistics

      Fornacon-Wood, I.; Mistry, H.; Johnson-Hart, C.; Faivre-Finn, C.; O'Connor, J. P. B.; Price, G. J. (2022)
    • Targeted Therapies for Perihilar Cholangiocarcinoma

      Gray, S.; Lamarca, A.; Edeline, J.; Klumpen, H. J.; Hubner, R. A.; McNamara, M. G.; Valle, J. W. (2022)
      Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
    • The economics of skin cancer prevention with implications for Australia and New Zealand: where are we now?

      Gordon, L. G.; Shih, S.; Watts, C.; Goldsbury, D.; Green, A. C. (2022)
      The incidence of skin cancer, including melanoma, continues to climb in white populations around the world, imposing a large and growing burden on health systems and individuals. Harmful exposure to ultraviolet (UV) radiation, mostly solar UV, is the most avoidable cause of skin cancer risk and mortality. Many economic evaluations attest to the favourable benefits for governments and citizens from skin cancer prevention programs. This overview presents the current ‘state of play’ of the economics of skin cancer prevention. More research is required to document contemporary costs of managing skin cancer in Australia and New Zealand to accurately assess the true savings from primary prevention. New directions are proposed for ways that economics could contribute to the investment case for prevention. The majority of skin cancers are avoidable and curable, yet cost the Australian health economy A$1.7 billion each year. Therefore primary prevention of skin cancers must remain high on the public health agenda.
    • Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

      Monteiro, C.; Miarka, L.; Perea-García, M.; Priego, N.; García-Gómez, P.; Álvaro-Espinosa, L.; de Pablos-Aragoneses, A.; Yebra, N.; Retana, D.; Baena, P.; et al. (2022)
      Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.
    • Prospektive Kohortenstudie von InspECT zur Sicherheit und Wirksamkeit der Elektrochemotherapie bei Hauttumoren und Metastasen in Abhängigkeit von Ulzeration

      Claussen, C. S.; Moir, G.; Bechara, F. G.; Orlando, A.; Matteucci, P.; Mowatt, D.; Clover, A. J. P.; Mascherini, M.; Gehl, J.; Muir, T.; et al. (2022)
      Hintergrund Elektrochemotherapie (ECT) ist eine wirksame lokale Behandlung von Hauttumoren. Ziel dieser Studie war es, die Wirksamkeit der ECT bei ulzerierten gegenüber nichtulzerierten Tumoren zu vergleichen und den Effekt auf tumorassoziierte Symptome zu untersuchen. Methodik 20 Krebszentren des International Network for Sharing Practices on Electrochemotherapy (InspECT) sammelten prospektiv Daten. Die ECT wurde nach dem ESOPE-Protokoll durchgeführt. Das Therapieansprechen wurde anhand der Entwicklung der Läsionsgröße bewertet. Zusätzlich wurden Schmerzen, Symptome, Leistungsstatus (ECOG-Index) und Gesundheitszustand (EQ-5D-Fragebogen) untersucht. Ergebnisse 716 Patienten mit ulzerierten (n = 302) und nichtulzerierten (n = 414) Hauttumoren und Metastasen wurden eingeschlossen (Mindest-Nachsorge 45 Tage). Nicht-ulzerierte Läsionen sprachen besser auf die ECT an als ulzerierte Läsionen (vollständiges Ansprechen: 65 % gegenüber 51 %, p = 0,0061). Nur 38 % (115/302) der Patienten mit ulzerierten Läsionen vor der ECT wiesen bei der letzten Nachuntersuchung ulzerierte Läsionen auf. Patienten mit ulzerierten Läsionen berichteten über stärkere Schmerzen und schwerere Symptome im Vergleich zu Patienten mit nichtulzerierten Läsionen, die sich nach der ECT signifikant und kontinuierlich besserten. Bei Patienten mit nichtulzerierten Läsionen hingegen nahmen die Schmerzen während der Behandlung vorübergehend zu. Es wurden keine schwerwiegenden Nebenwirkungen beobachtet. Schlussfolgerungen Die ECT ist eine sichere und wirksame lokale Behandlung von Hauttumoren. Während die ECT die Symptome insbesondere bei Patienten mit ulzerierten Läsionen verbessert, sollte auf Basis der Daten die Implementation eines perioperativen Schmerzmanagements besonders bei nichtulzerierten Läsionen während der ECT erwogen werden.
    • Radial Data Mining to Identify Density-Dose Interactions That Predict Distant Failure Following SABR

      Davey, A.; van Herk, M.; Faivre-Finn, C.; McWilliam, A. (2022)
      Purpose: Lower dose outside the planned treatment area in lung stereotactic radiotherapy has been linked to increased risk of distant metastasis (DM) possibly due to underdosage of microscopic disease (MDE). Independently, tumour density on pretreatment computed tomography (CT) has been linked to risk of MDE. No studies have investigated the interaction between imaging biomarkers and incidental dose. The interaction would showcase whether the impact of dose on outcome is dependent on imaging and, hence, if imaging could inform which patients require dose escalation outside the gross tumour volume (GTV). We propose an image-based data mining methodology to investigate density–dose interactions radially from the GTV to predict DM with no a priori assumption on location. Methods: Dose and density were quantified in 1-mm annuli around the GTV for 199 patients with early-stage lung cancer treated with 60 Gy in 5 fractions. Each annulus was summarised by three density and three dose parameters. For parameter combinations, Cox regressions were performed including a dose–density interaction in independent annuli. Heatmaps were created that described improvement in DM prediction due to the interaction. Regions of significant improvement were identified and studied in overall outcome models. Results: Dose–density interactions were identified that significantly improved prediction for over 50% of bootstrap resamples. Dose and density parameters were not significant when the interaction was omitted. Tumour density variance and high peritumour density were associated with DM for patients with more cold spots (less than 30-Gy EQD2) and non-uniform dose about 3 cm outside of the GTV. Associations identified were independent of the mean GTV dose. Conclusions: Patients with high tumour variance and peritumour density have increased risk of DM if there is a low and non-uniform dose outside the GTV. The dose regions are independent of tumour dose, suggesting that incidental dose may play an important role in controlling occult disease. Understanding such interactions is key to identifying patients who will benefit from dose-escalation. The methodology presented allowed spatial dose–density interactions to be studied at the exploratory stage for the first time. This could accelerate the clinical implementation of imaging biomarkers by demonstrating the impact of incidental dose for tumours of varying characteristics in routine data.
    • Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study)

      Van der Weijst, L.; Aguado-Barrera, M. E.; Azria, D.; Berkovic, P.; Boisselier, P.; Briers, E.; Bultijnck, R.; Calvo-Crespo, P.; Chang-Claude, J.; Choudhury, A.; et al. (2022)
      Objectives Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study. Materials and methods HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages. Results Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually. Conclusions While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals’ HRQoL, symptoms and toxicity in treatment decision-making.
    • Plasma Tie2 trajectories identify vascular response criteria for VEGF inhibitors across advanced biliary tract, colorectal and ovarian cancers

      Zhou, C.; O'Connor, J.; Backen, A.; Valle, J. W.; Bridgewater, J.; Dive, C.; Jayson, G. C. (2022)
      Background Vascular endothelial growth factor inhibitors (VEGFi) are compromised by a lack of validated biomarkers. Previously we showed that changes in the concentration of plasma Tie2 (pTie2) was a response biomarker for bevacizumab. Here, we investigated whether pTie2 can predict response and progression cross-tumour for generic VEGFi treatment. Patients and methods Patients (n = 124) with advanced biliary tract cancer (ABC) received cisplatin/gemcitabine with cediranib or placebo (ABC-03 trial). Concentrations of pTie2 were measured longitudinally from before treatment until disease progression. Data from patients with ovarian cancer (n = 92, ICON7 trial) and patients with colorectal cancer (CRC) (n = 70, Travastin trial) were also included. Results Cediranib-treated ABC patients were deconvoluted into distinct groups where in one group pTie2 trajectories resembled those seen in placebo-treated patients and in another pTie2 significantly reduced (t-test P = 2.7 × 10−14). Using the 95% confidence interval for these two groups, we defined a vascular complete response (vCR) as a 24% reduction in pTie2 within 9 weeks; vascular no response (vNR) as a 7% increase in pTie2, and a vascular partial response (between these limits). vCR cediranib-treated patients had significantly improved progression-free survival (8.8 versus 7.5 months, restricted mean ratio 0.73, P = 0.012) and overall survival (18.8 versus 12.1 months, hazard ratio 0.49, P = 0.02). By integrating data across ovarian cancer, CRC and ABC, we show that (i) patients with vNR do not benefit from VEGFi and (ii) Tie2-defined vascular progression occurs sufficiently in advance of radiological progressive disease that changes in treatment could be offered to prevent clinical deterioration. Conclusion pTie2 is the first cross-tumour, generic VEGFi, vascular response biomarker to guide optimum use of VEGFi in clinical practice.
    • Prospective cohort study by InspECT on safety and efficacy of electrochemotherapy for cutaneous tumors and metastases depending on ulceration

      Claussen, C. S.; Moir, G.; Bechara, F. G.; Orlando, A.; Matteucci, P.; Mowatt, D.; Clover, A. J. P.; Mascherini, M.; Gehl, J.; Muir, T.; et al. (2022)
      Background Electrochemotherapy (ECT) is an effective local treatment for cutaneous tumors. The aim of this study was to compare the effectiveness of ECT in ulcerated vs. non-ulcerated tumors and investigate the effect on tumor-associated symptoms. Methods Twenty cancer centers in the International Network for Sharing Practices on Electrochemotherapy (InspECT) prospectively collected data. ECT was performed following ESOPE protocol. Response was evaluated by lesion size development. Pain, symptoms, performance status (ECOG-Index) and health status (EQ-5D questionnaire) were evaluated. Results 716 patients with ulcerated (n = 302) and non-ulcerated (n = 414) cutaneous tumors and metastases were included (minimum follow-up of 45 days). Non-ulcerated lesions responded to ECT better than ulcerated lesions (complete response 65 % vs. 51 %, p = 0.0061). Only 38 % (115/302) with ulcerated lesions before ECT presented with ulcerated lesions at final follow-up. Patients with ulcerated lesions reported higher pain and more severe symptoms compared to non-ulcerated lesions, which significantly and continuously improved following ECT. In non-ulcerated lesions however, pain spiked during the treatment. No serious adverse events were reported. Conclusions ECT is a safe and effective local treatment for cutaneous tumors. While ECT improves symptoms especially in patients with ulcerated lesions, data suggest the implementation of a perioperative pain management in non-ulcerated lesions during ECT.