• REQUITE: a prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

      Seibold, P; Webb, A; Aguado-Barrera, ME; Azria, D; Bourgier, C; Brengues, M; Briers, E; Bultijnck, R; Calvo-Crespo, P; Carballo, A; et al. (2019)
      PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n?=?4409) and PAXgene tubes (n?=?3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ³2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.
    • Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group

      Hoeben, B; Carrie, C; Timmermann, B; Mandeville, H; Gandola, L; Dieckmann, K; Ramos, A; Magelssen, H; Lassen-Ramshad, Y; Ondrova, B; et al. (2019)
      Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.
    • European cholangiocarcinoma (EU-CCA) registry: An initiative to broaden awareness on the second most common primary liver cancer

      Santos-Laso, A; Lamarca, Angela; La Casta, A; Braconi, C; Adeva, J; Evert, M; Forner, A; Macias, R; Krawczyk, M; Izquierdo-Sanchez, L; et al. (2019)
    • The case for screening all endometrial cancer patients for lynch syndrome

      Ryan, N; Glaire, M; Ramchander, N; Davison, N; Walker, T; Donnelly, L; McMahon, R; Tobi, S; Wallace, A; Payne, K; et al. (2019)
    • Electrochemotherapy of superficial tumors - current status: basic principles, operating procedures, shared indications, and emerging applications

      Campana, L; Miklavcic, D; Bertino, G; Marconato, R; Valpione, Sara; Imarisio, I; Dieci, M; Granziera, E; Cemazar, M; Alaibac, M; et al. (2019)
      Treatment of superficial tumors with electrochemotherapy (ECT) has shown a steep rise over the past decade and indications range from skin cancers to locally advanced or metastatic neoplasms. Based on reversible electroporation, which is a physical method to achieve transient tumor cell membrane permeabilization by means of short electric pulses, ECT increases cellular uptake of bleomycin and cisplatin and their cytotoxicity by 8,000- and 80-fold, respectively. Standard operating procedures were established in 2006 and updated in 2018. Ease of administration, patient tolerability, efficacy across histotypes, and repeatability are peculiar advantages, which make standard ECT (ie, ECT using fixed-geometry electrodes) a reliable option for controlling superficial tumor growth locally and preventing their morbidity. Consolidated indications include superficial metastatic melanoma, breast cancer, head and neck skin tumors, nonmelanoma skin cancers, and Kaposi sarcoma. In well-selected patients with oropharyngeal cancers, ECT ensures appreciable symptom control. Emerging applications include skin metastases from visceral or hematological malignancies, vulvar cancer, and some noncancerous skin lesions (keloids and capillary vascular malformations). Repeatability and integration with other oncologic therapies allow for consolidation of response and sustained tumor control. In this review, we present the basic principles of ECT, recently updated operating procedures, anesthesiological management, and provide a synthesis of the efficacy of standard ECT across histotypes.
    • Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial

      Judson, I; Morden, JP; Kilburn, L; Leahy, Michael G; Benson, C; Bhadri, V; Campbell-Hewson, Q; Cubedo, R; Dangoor, A; Fox, L; et al. (2019)
      BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34á3 months (IQR 23á7-55á6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8á3% (IQR -26á5 to 5á9) with cediranib versus 13á4% (IQR 1á1 to 21á3) with placebo (one-sided p=0á0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.
    • Patient-reported outcome results from the open-label, randomized phase III myeloma X trial evaluating salvage autologous stem-cell transplantation in relapsed multiple myeloma

      Ahmedzai, SH; Snowden, JA; Ashcroft, AJ; Cairns, DA; Williams, C; Hockaday, A; Cavenagh, JD; Ademokun, D; Tholouli, E; Allotey, D; et al. (2019)
      PURPOSE: Salvage autologous stem-cell transplantation (sASCT) in patients with multiple myeloma (MM) relapsing after a prior autologous stem-cell transplantation leads to increased remission duration and overall survival. We report a comprehensive study on patient-reported outcomes, including quality of life (QoL) and pain in sASCT. METHODS: Patients were randomly assigned to either sASCT or nontransplantation consolidation (NTC). Pain and QoL were assessed as secondary outcomes using validated QoL instruments (European Organisation for Research and Treatment of Cancer QLQ-C30 and myeloma-specific module, QLQ-MY20; the Brief Pain Inventory [Short Form]; and the Leeds Assessment of Neuropathic Symptoms and Signs [Self-Assessment] scale). RESULTS: A total of 288 patients (> 96%) consented to the QoL substudy. The median follow-up was 52 months. The European Organisation for Research and Treatment of Cancer QLQ-C30 Global health status scores were higher (better) in the NTC group at 100 days after random assignment ( P = .0496), but not at later time points. Pain interference was higher (worse) in the sASCT group than in the NTC group at 6 months after random assignment ( P = .0267), with patients with sASCT reporting higher scores for Pain interference with daily living for up to 2 years after random assignment. Patients reporting lower concerns about adverse effects of treatment after sASCT had a time to progression advantage. CONCLUSION: Patients with sASCT with relapsed MM demonstrated a comparative reduction in QoL and greater impact of treatment adverse effects lasting for 6 months and up to 2 years for pain, after which patients who had received sASCT reported better outcomes. Patients who experienced lower adverse effects after sASCT had longer time to progression and overall survival, showing the need to improve symptom management peritransplantation. To our knowledge, this study provides the most comprehensive picture of QoL before and after sASCT in patients with relapsed MM.
    • Early demise from high grade serous ovarian cancer is predictable and likely related to tumour biology

      Hawarden, A; Russell, B; Gee, M; Skayali, F; Edmondson, M; Clamp, Andrew R; Jayson, Gordon C; Crosbie, E; Edmondson, R; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary’s Hospital,Manchester, UK (2019)
    • An evaluation of cetuximab dosing strategies using pharmacokinetics and cost analysis

      Ogungbenro, Kayode; Patel, Alkesh; Saunders, Mark P; Clark, James; Duncombe, Robert; Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK (2019)
      OBJECTIVES: Cetuximab dosing is based on body surface area (BSA), an approach that is associated with significant wastage due to available vial sizes. NHS England recently introduced an alternative strategy for cetuximab dosing based on dose banding. The aim of this work was to investigate approaches to cetuximab dosing to improve its cost-effectiveness. METHODS: A simulation study using a population pharmacokinetic model was used to assess the performance of dosing strategies using exposure, probability of target attainment and cost. Two dosage regimens (500 and 400/250 mg/m2 ) were investigated; 5% and 10% dose banding, fixed and optimised dosing strategies were evaluated and compared to BSA strategy. KEY FINDINGS: The percentage of the total cost associated with wastage for the 400/250 mg/m2 regimen were 8.75%, 5.13%, 3.61%, 9.2% and 0% for BSA; 5 and 10% bands; fixed and optimal strategies, respectively. Similar results were obtained for 500 mg/m2 regimen. In comparison with BSA strategy, other strategies have comparable or improved performance. Optimised strategy showed consistent performance and ensures equal exposure and probability of target attainment. CONCLUSIONS: Cost-effectiveness of cetuximab treatment can be improved with alternative strategies by reducing wastage without compromising exposure.
    • SAMBA18 report - a national audit of acute medical care in the UK

      Lasserson, D; Subbe, C; Cooksley, Timothy J; Holland, M; University of Birmingham, UK (2019)
      SAMBA18 took place on Thursday 28th June 2018 with follow up data at 7 days. Acute medical teams from 127 Acute Medical Units (AMUs) across the UK collected data relating to operational performance, clinical quality indicators and standards from NHS Improvement. Data was collected from 6114 patients
    • Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): modelling to estimate long-term survival, quality-adjusted survival, and cost-effectiveness

      Woods, BS; Sideris, E; Sydes, MR; Gannon, MR; Parmar, MKB; Alzouebi, M; Attard, G; Birtle, AJ; Brock, S; Cathomas, R; et al. (2019)
    • Oxygen-enhanced MRI is feasible, repeatable, and detects radiotherapy-induced change in hypoxia in xenograft models and in patients with non-small cell lung cancer

      Salem, Ahmed; Little, R; Latif, A; Featherstone, A; Babur, M; Peset, Isabel; Cheung, S; Watson, Y; Tessyman, V; Mistry, Hitesh; et al. (2019)
      Purpose: Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently.Experimental Design: We evaluated the ability of oxygen-enhanced MRI (OE-MRI) to map and quantify therapy-induced changes in tumor hypoxia by measuring oxygen-refractory signals in perfused tissue (perfused Oxy-R). Clinical first-in-human study in patients with non-small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model).Results: MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy (P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858-0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy (P = 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors.Conclusions: These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia.
    • Association of multidimensional comorbidities with survival, toxicity, and unplanned hospitalizations in older adults with metastatic colorectal cancer treated with chemotherapy

      Kim, KH; Lee, JJ; Kim, J; Zhou, JM; Gomes, Fabio; Sehovic, M; Extermann, M; Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea (2019)
      BACKGROUND: Studies of older patients with colorectal cancer(CRC) have found inconsistent results about the correlation of various comorbidities with overall survival(OS) and treatment tolerance. To refine our understanding, we evaluated this correlation using the Cumulative Illness Rating Scale-Geriatric(CIRS-G) and heat maps to identify subgroups with the highest impact. METHODS: We retrospectively reviewed 153 patients aged 65?years and older with stage IV CRC undergoing chemotherapy. We calculated CIRS-G scores, and a Total Risk Score(TRS) derived from a previous heat map study. The association between CIRS-G scores/TRS and OS, unplanned hospitalizations, and chemotoxicity was examined by the Cox proportional hazards model. RESULTS: Median age was 71?years. Median MAX2 score of chemotherapies was 0.134(0.025-0.231). The most common comorbidities were vascular(79.8%), eye/ear/nose/throat(68%), and respiratory disease(52.4%). Median OS was 25.1?months(95% confidence interval: 21.2-27.6). In univariate analysis, ECOG PS???2(HR 1.86(1.1-3.17), p?=?0.019), poorly differentiated histology(HR 2.03(1.27-3.25), p?=?0.003), primary site(rectum vs colon)(HR 0.58 (0.34-0.98), p?=?0.04), age at diagnosis(HR per 5y 1.20 (1.04-1.39), p?=?0.012), and number of CIRS-G grade 4 comorbidities(HR 1.86 (1.1-3.17), p?=?0.019) were associated with OS. In multivariate analysis, the number of CIRS-G grade 4 comorbidities lost significance, although it retained it in the subgroup of patients with colon cancer. Conversely, the TRS was associated with OS in patients with rectal cancer. No association of comorbidity with unplanned hospitalization or chemotoxicity was observed. CONCLUSIONS: In older adults with metastatic CRC, the number of CIRS-G grade 4 comorbidities was associated with worse OS but no specific CIRS-G category was independently associated with OS, unplanned hospitalization, or toxicities.
    • Characteristics associated with significantly worse quality of life in mycosis fungoides/Sezary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study

      Molloy, K; Jonak, C; Woei, AJF; Guenova, E; Busschots, AM; Bervoets, A; Hauben, E; Knobler, R; Porkert, S; Fassnacht, C; et al. (2019)
      BACKGROUND: Mycosis fungoides (MF) and Sézary Syndrome (SS) are the most common cutaneous T-cell lymphomas. MF/SS is accompanied by considerable morbidity from pain, itching and disfigurement. AIM: To identify factors associated with poorer health-related quality of life (HRQoL) in newly diagnosed MF/SS patients. METHODS: Patients enrolled into PROCLIPI (an international observational study in MF/SS) had HRQoL assessed using the Skindex-29 questionnaire. Skindex-29 scores were analysed in relation to patient-specific and disease-specific characteristics. RESULTS: The study population consisted of 237 patients (60·3% male) with a median age of 60 years (IQR 49-70yrs), of whom 179 had early MF and 58 had advanced MF/SS. In univariate analysis, HRQoL as measured by Skindex-29 was worse in females, SS, late-stage MF, those with elevated LDH, alopecia, high mSWAT and confluent erythema. Linear regression models only identified female gender (?=8·61, p=0·003) and alopecia (?=9·71, p=0·02) as independent predictors for worse global HRQoL. In item-level analysis showed that the severe impairment in symptoms (OR 2·14, 95% CI 1·19-3·89) and emotions (OR 1·88, 95% CI 1·09-3·27) subscale scores seen in female patients was caused by more burning/stinging, pruritus, irritation and greater feelings of depression, shame, embarrassment and annoyance with their diagnosis of MF/SS. CONCLUSION: HRQoL is significantly more impaired in newly diagnosed female patients with MF/SS and in those with alopecia. As Skindex-29 does not include existential questions on cancer which may cause additional worry and distress, a comprehensive validated CTCL specific questionnaire is urgently needed to more accurately assess disease-specific HRQoL among these patients. This article is protected by copyright. All rights reserved.
    • Revised international surveillance case definition of transfusion-associated circulatory overload: a classification agreement validation study

      Wiersum-Osselton, J; Whitaker, B; Grey, S; Land, K; Perez, G; Rajbhandary, S; Andrzejewski, C; Bolton-Maggs, P; Lucero, Harriet; Renaudier, P; et al. (2019)
      BACKGROUND: Transfusion-associated circulatory overload (TACO) is a major cause of transfusion-related morbidity and mortality in countries with well developed transfusion services. The International Society of Blood Transfusion, the International Haemovigilance Network, and AABB (formerly American Association of Blood Banks), have developed and validated a revised definition of TACO. METHODS: International Haemovigilance Network-member haemovigilance systems (Australia, Austria, Denmark, Finland, Greece, India, Ireland, Italy, Japan, Malta, Netherlands, New Zealand, Norway, Slovenia, United Kingdom and United States) provided cases of respiratory complications categorised by their systems, including clinical parameters listed in the 2017 draft definition (part 1). Individual transfusion professionals were then invited to assess 24 case descriptions according to the draft definition (part 2). Positive and negative agreement and inter-rater agreement (?) were calculated. Based on validation results, cases were reanalysed and slight adjustments made to yield the final 2018 TACO definition. FINDINGS: In part 1, 16 (44%) of 36 haemovigilance systems provided 178 cases, including 126 TACO cases. By use of the 2018 definition, 96 (76%) of 126 cases of TACO were in positive agreement. 19 (37%) of 52 cases were recognised as non-TACO respiratory complications. In part 2 (47 experts from 20 countries), moderate all-case agreement (?=0·43) and TACO-specific agreement (?=0·54) were observed. Excluding cases missing some clinical information (eg, N terminal pro-brain natriuretic peptide, distinctive chest x-ray findings, and relationship with existing respiratory co-morbidities like pneumonia and chronic obstructive pulmonary disease) improved all-case agreement to ?=0·50 (moderate) and ?=0·65 (good) for TACO cases. INTERPRETATION: The two-part validation exercise showed that the revised 2018 TACO surveillance case definition captures 76% of cases endorsed as TACO by participating haemovigilance systems. This definition can become the basis for internationally consistent surveillance reporting and contribute towards increased awareness and mitigation of TACO. Further research will require reporting more complete clinical information to haemovigilance systems and should focus on improved distinction between TACO and other transfusion respiratory complications.
    • Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

      Bedognetti, D; Ceccarelli, M; Galluzzi, L; Lu, R; Palucka, K; Samayoa, J; Spranger, S; Warren, S; Wong, K; Ziv, E; et al. (2019)
      Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.
    • Prospective observational study of pazopanib in patients with advanced renal cell carcinoma (PRINCIPAL study)

      Schmidinger, M; Bamias, A; Procopio, G; Hawkins, Robert E; Sanchez, A; Vazquez, S; Srihari, N; Kalofonos, H; Bono, P; Pisal, C; et al. (2019)
      BACKGROUND: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). SUBJECTS, MATERIALS, AND METHODS: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30?days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. RESULTS: Six hundred fifty-seven patients were enrolled and received ?1 dose of pazopanib. Median PFS and OS were 10.3?months (95% confidence interval [CI], 9.2-12.0) and 29.9?months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. CONCLUSION: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. IMPLICATIONS FOR PRACTICE: PRINCIPAL is the largest (n?=?657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors' knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10?months and generally survive for nearly 30?months.
    • Impact of concomitant administration of gastric acid-suppressive agents and Pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials

      Mir, O; Touati, N; Lia, M; Litiere, S; Le, CA; Sleijfer, S; Blay, JY; Leahy, Michael G; Young, R; Mathijssen, RHJ; et al. (2019)
      PURPOSE: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects. PATIENTS AND METHODS: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ?80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients. RESULTS: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS). CONCLUSIONS: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.
    • Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial

      Rini, B; Powles, T; Atkins, M; Escudier, B; McDermott, D; Suarez, C; Bracarda, S; Stadler, W; Donskov, F; Lee, J; et al. (2019)
      BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. FINDINGS: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. INTERPRETATION: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.
    • SABR versus conventional fractionation regimens in NSCLC

      Joseph, N; Choudhury, Ananya; Ministry of Health, Colombo 01000, Sri Lanka. (2019)