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  • FLASH radiotherapy involves delivering ultra-high dose rates of radiation, which enables sustained tumour control with reduced toxicity to surrounding tissues. The authors of this Perspective describe the principles underlying FLASH radiotherapy, present the available evidence from preclinical studies testing this modality and discuss the challenges for its application in routine clinical practice.

    • Marie-Catherine Vozenin
    • Jean Bourhis
    • Marco Durante
  • Glioblastoma, the most common form of brain cancer in adults, has a dismal prognosis and has proven recalcitrant to novel targeted therapies and immunotherapies. Extrachromosomal DNAs (ecDNAs) harbouring oncogenes are increasingly recognized as important drivers of tumour development, evolution and resistance to treatment, particularly in patients with glioblastoma. In this Perspective, the authors summarize key reasons for the failed clinical translation of new therapies for glioblastoma, highlighting the important contributions of ecDNAs. They then focus on the opportunities and challenges of utilizing ecDNAs to improve the likelihood of success in the development of precision medicines for this disease.

    • Imran Noorani
    • Paul S. Mischel
    • Charles Swanton
  • Liquid biopsy assays of diverse cancer-associated molecular alterations in blood, including genomic, epigenomic, transcriptomic, proteomic and metabolomics changes, offer considerable opportunities for early detection of cancer as well as improved management of the disease. In this Perspective, the authors review key advances in liquid biopsy-based multi-omics approaches for biomarker discovery. They also introduce the ‘nano-omics’ paradigm, whereby nanotechnology tools are used to capture and enrich various cancer-derived analytes from biofluids for subsequent omics analyses, with the aim of developing novel biomarker panels for early cancer detection.

    • Lois Gardner
    • Kostas Kostarelos
    • Marilena Hadjidemetriou
  • In this Perspective, Nathan Cherny appraises the FDA approvals of therapeutic agents granted for use in adult patients with solid tumours during the 5 years 2017–2021 against the aspirations of the Cancer Moonshot, in terms of sheer number of approvals, the strength of the supporting evidence and the magnitude of clinical benefit. He also outlines areas where improvements are needed to more confidently ensure that the clinical benefits of approved treatments justify the associated risks.

    • Nathan I. Cherny
  • Immune-checkpoint inhibitors are associated with a unique spectrum of organ-specific inflammatory toxicities known as immune-related adverse events (irAEs). In the past few years, aggregate clinical data, real-world data and multi-omics data have been used to investigate the underlying mechanisms and clinical presentations of irAEs. The authors of this Perspective summarize the knowledge on irAEs that has been obtained from different sources of ‘big data’.

    • Ying Jing
    • Jingwen Yang
    • Leng Han
  • In oncology, a definition of drug value that patients, payers, regulators and clinicians agree upon on does not exist. The authors of this Perspective discuss different approaches to measuring value, such as assessments of benefit–risk balance and cost-effectiveness, individual attitudes to risk, and use of scales developed to measure value objectively. They also explain how regulators can help to inform different decision makers.

    • Francesco Pignatti
    • Ulla Wilking
    • Jonas Bergh
  • Prognostication of outcome across multiple cancers and prediction of response to various treatment modalities are among the next generation of challenges that artificial intelligence (AI) tools can solve using radiology images. The authors of this Perspective describe the evolution of AI-based approaches in oncology imaging and address the path to their adoption as decision-support tools in the clinic.

    • Kaustav Bera
    • Nathaniel Braman
    • Anant Madabhushi
  • Patients with primary central nervous system (CNS) malignancies largely do not derive benefit from immune-checkpoint inhibitors. Paradoxically, a subset of those with CNS metastases from tumours located outside of the CNS will respond to the same approach. In this Perspective, the authors explore the key differences in the immune cell composition of primary CNS malignancies and brain metastases and provide guidance on potential alternative immunotherapies that might be effective in patients with these historically difficult-to-treat malignancies.

    • Martina Ott
    • Robert M. Prins
    • Amy B. Heimberger
  • Assuming that the latest incidence trends continue for the major cancer types, the incidence of all cancers combined will double by 2070 relative to 2020, with the greatest increases predicted in lower-resource settings. The authors of this Perspective discuss how population-level approaches with amenable goals should be considered an integral part of cancer control.

    • Isabelle Soerjomataram
    • Freddie Bray
  • Immune responses against tumour antigens that do not arise from cancer cell-specific mutations can result in autoimmune reactions against the tissue of origin of the tumour. Despite their undesirable effects, these symptoms can have prognostic value and correlate with favourable disease outcomes. The authors of this Perspective discuss the importance of such beneficial autoimmunity in patients with advanced-stage disease and in cancer immunosurveillance.

    • Laurence Zitvogel
    • Claude Perreault
    • Guido Kroemer
  • Anti-angiogenic therapy has the capacity to ameliorate antitumour immunity and, thus, some combinations of anti-angiogenics and immunotherapies have been approved and a number of them are being tested. The authors of this Perspective describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as a vascular counterpart of immune checkpoints.

    • Zowi R. Huinen
    • Elisabeth J. M. Huijbers
    • Arjan W. Griffioen
  • In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.

    • Abhijit Pal
    • Rajiv Shinde
    • Johann de Bono
  • Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

    • Aakash Desai
    • Justin F. Gainor
    • Vivek Subbiah
  • Liquid biopsy assays have the potential to revolutionize the diagnosis and management of cancer, and rapid progress is being made in the clinical translation of such assays. This Perspective outlines notable advances in the use of liquid biopsy technologies in the management of solid tumours, as well as future research avenues, clinical trial methodologies and implementation logistics for the eventual integration of liquid biopsy into the clinical workflow.

    • Michail Ignatiadis
    • George W. Sledge
    • Stefanie S. Jeffrey
  • The availability of ever more sensitive cell sorting and sequencing technologies has enabled the interrogation of tumour cell biology at the highest possible level of resolution — analysis of a single cell. In this Perspective, the authors describe the application of such approaches to the analysis of single tumour-associated immune cells and their potential for improving the outcomes in patients receiving anti-cancer immunotherapies.

    • Satyen H. Gohil
    • J. Bryan Iorgulescu
    • Kenneth J. Livak
  • The incidence of early-onset colorectal cancer (CRC) is increasing worldwide for reasons that are currently unclear. Herein, the authors review the current epidemiological, clinical, pathological and molecular understanding of early-onset CRC that occurs in patients ≥50 years of age, drawing contrasts with later-onset CRC. They also discuss future research strategies for improved understanding, prevention, early detection and clinical management of early-onset CRC.

    • Naohiko Akimoto
    • Tomotaka Ugai
    • Shuji Ogino
  • Genotyping is recommended for all patients with metastatic non-squamous non-small-cell lung cancers (NSCLC), both to enable patients to receive targeted therapies and to avoid therapies they are unlikely to benefit from. However, obtaining tumour biopsy material for genotyping is often challenging and is unfeasible in some patients, indicating the need to incorporate liquid biopsy approaches. In this Perspective, the authors provide guidance on how analysis of ctDNA from liquid biopsy samples in patients with metastatic NSCLC prior to first-line therapy has the potential to extend the benefits of genotyping to virtually all patients.

    • Charu Aggarwal
    • Christian D. Rolfo
    • David R. Gandara
  • The possible uses of artificial intelligence (AI) in radiation oncology are diverse and wide ranging. Herein, the authors discuss the potential applications of AI at each step of the radiation oncology workflow, which might improve the efficiency and overall quality of radiation therapy for patients with cancer. The authors also describe the associated challenges and provide their perspective on how AI platforms might change the roles of radiation oncology medical professionals.

    • Elizabeth Huynh
    • Ahmed Hosny
    • Raymond H. Mak
  • The availability and subsequent successes of immune-checkpoint inhibitors (ICIs) in patients with metastatic melanoma, and to a lesser extent in those with several other forms of cancer, have made long-term treatment-free remissions a realistic possibility for a subset of patients. In this Perspective, the authors describe available data on long-term remission from patients with melanoma and other solid tumours and provide early recommendations regarding the circumstances in which ICIs can be safely discontinued.

    • Caroline Robert
    • Aurelien Marabelle
    • Benjamin Besse
  • Monitoring both cancer incidence and death rates is important for guiding health policy and the direction of future research. In this Perspective, the authors describe changes in cancer incidence and death rates in the USA, highlighting the effects of specific policies and research developments, and providing insight into unmet needs that should be addressed by future health policies.

    • Farhad Islami
    • Rebecca L. Siegel
    • Ahmedin Jemal