Explore the vast range of titles available.

The ultimate goal of radiation oncology is to eradicate tumours without toxicity to non-malignant tissues. FLASH radiotherapy, or the delivery of ultra-high dose rates of radiation (>40 Gy/s), emerged as a modality of irradiation that enables tumour control to be maintained while reducing toxicity to surrounding non-malignant tissues. In the past few years, preclinical studies have shown that FLASH radiotherapy can be delivered in very short times and substantially can widen the therapeutic window of radiotherapy. This ultra-fast radiation delivery could reduce toxicity and thus enable dose escalation to enhance antitumour efficacy, with the additional benefits of reducing treatment time and organ motion-related issues, eventually increasing the number of patients who can be treated. At present, FLASH is recognized as one of the most promising breakthroughs in radiation oncology, standing at the crossroads between technology, physics, chemistry and biology; however, several hurdles make its clinical translation difficult, including the need for a better understanding of the biological mechanisms, optimization of parameters and technological challenges. In this Perspective, we provide an overview of the principles underlying FLASH radiotherapy and discuss the challenges along the path towards its clinical application.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.

Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics — the combination of diagnostic imaging with targeted therapy — is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.Radiotheranostics enables the clinician to image and then target lesions using the same probe. Despite this appealing potential, interest in the field of radiotheranostics has long been constrained by a lack of expertise, high infrastructure costs and the availability of non-radioactive alternative approaches. Nonetheless, several recent successes have led to renewed research interest. In this Review, the authors summarize the current challenges and opportunities in this rapidly emerging area.

Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient’s T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.Chimeric antigen receptor T cells have revolutionized the treatment of patients with certain haematological malignancies. Nonetheless, an optimal approach to lymphodepleting chemotherapy and/or bridging therapies has yet to be defined in patients receiving these agents. In this Review, the authors describe the various lymphodepletion and/or bridging therapy strategies used, and highlight the need for prospective comparisons in order to determine the safest and most effective approach.

During the COVID-19 global pandemic, the cancer community faces many difficult questions. We will first discuss safety considerations for patients with cancer requiring treatment in SARS-CoV-2 endemic areas. We will then discuss a general framework for prioritizing cancer care, emphasizing the precautionary principle in decision making.

Surgical resection combined with systemic chemotherapy is the cornerstone of treatment for patients with localized pancreatic cancer. Upfront surgery is considered suboptimal in cases with extensive vascular involvement, which can be classified as either borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In these patients, FOLFIRINOX or gemcitabine plus nab-paclitaxel chemotherapy is currently used as preoperative chemotherapy and is eventually combined with radiotherapy. Thus, more patients might reach 5-year overall survival. Patient selection for chemotherapy, radiotherapy and subsequent surgery is based on anatomical, biological and conditional parameters. Current guidelines and clinical practices vary considerably regarding preoperative chemotherapy and radiotherapy, response evaluation, and indications for surgery. In this Review, we provide an overview of the clinical evidence regarding disease staging, preoperative therapy, response evaluation and surgery in patients with borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In addition, a clinical work-up is proposed based on the available evidence and guidelines. We identify knowledge gaps and outline a proposed research agenda. In this Review, Besselink and colleagues discuss preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer, including disease staging and response evaluation. Key points Preoperative multi-agent chemotherapy (for example, FOLFIRINOX or gemcitabine plus nab-paclitaxel) is now routinely used in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC), both to obtain local and systemic control and to select suitable candidates for surgery. Considerable variation exists among national and international guidelines and clinical practices regarding preoperative therapy in patients with BRPC or LAPC, including the type and duration of chemotherapy and the role, type, and timing of radiotherapy; a uniform, evidence-based international guideline with support from all relevant societies is needed. Three randomized controlled trials reported improved outcomes with neoadjuvant chemotherapy or chemoradiotherapy compared with upfront surgery in patients with BRPC; more randomized trials assessing the effect of modern multi-agent chemotherapy and radiotherapy are needed and several are ongoing. Response evaluation after preoperative chemotherapy and chemoradiotherapy is a major challenge as conventional cross-sectional imaging mostly underestimates the tumour response. Biological response evaluation is therefore advised (particularly a relative decrease of serum CA19-9). However, there is an urgent need for more accurate tumour markers. Surgery after preoperative therapy in patients with BRPC and LAPC requires high-volume expertise for patient selection, intraoperative decision-making, extended resections and postoperative care; preoperative counselling and shared decision-making are crucial.

Owing to advances in radiotherapy, the physical properties of radiation can be optimized to enable individualized treatment; however, optimization is rarely based on biological properties and, therefore, treatments are generally planned with the assumption that all tumours respond similarly to radiation. Radiation affects multiple cellular pathways, including DNA damage, hypoxia, proliferation, stem cell phenotype and immune response. In this Review, we summarize the effect of these pathways on tumour responses to radiotherapy and the current state of research on genomic classifiers designed to exploit these variations to inform treatment decisions. We also discuss whether advances in genomics have generated evidence that could be practice changing and whether advances in genomics are now ready to be used to guide the delivery of radiotherapy alone or in combination.Although radiotherapy affects multiple cellular pathways, treatments are generally planned with the assumption that all tumours respond similarly to radiation. The authors of this Review summarize the effect of various pathways activated by radiotherapy on tumour responses to radiotherapy and present the current knowledge on genomic classifiers designed to inform treatment decisions.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and continues to portend poor survival, despite multimodal treatment using surgery and chemoradiotherapy. The addition of tumour-treating fields (TTFields)—an approach in which alternating electrical fields exert biophysical force on charged and polarisable molecules known as dipoles—to standard therapy, has been shown to extend survival for patients with newly diagnosed GBM, recurrent GBM and mesothelioma, leading to the clinical approval of this approach by the FDA. TTFields represent a non-invasive anticancer modality consisting of low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), alternating electric fields delivered via cutaneous transducer arrays configured to provide optimal tumour-site coverage. Although TTFields were initially demonstrated to inhibit cancer cell proliferation by interfering with mitotic apparatus, it is becoming increasingly clear that TTFields show a broad mechanism of action by disrupting a multitude of biological processes, including DNA repair, cell permeability and immunological responses, to elicit therapeutic effects. This review describes advances in our current understanding of the mechanisms by which TTFields mediate anticancer effects. Additionally, we summarise the landscape of TTFields clinical trials across various cancers and consider how emerging preclinical data might inform future clinical applications for TTFields.

With the advancement of treatment modalities in radiation therapy for cancer patients, outcomes have improved, but at the cost of increased treatment plan complexity and planning time. The accurate prediction of dose distributions would alleviate this issue by guiding clinical plan optimization to save time and maintain high quality plans. We have modified a convolutional deep network model, U-net (originally designed for segmentation purposes), for predicting dose from patient image contours of the planning target volume (PTV) and organs at risk (OAR). We show that, as an example, we are able to accurately predict the dose of intensity-modulated radiation therapy (IMRT) for prostate cancer patients, where the average Dice similarity coefficient is 0.91 when comparing the predicted vs. true isodose volumes between 0% and 100% of the prescription dose. The average value of the absolute differences in [max, mean] dose is found to be under 5% of the prescription dose, specifically for each structure is [1.80%, 1.03%](PTV), [1.94%, 4.22%](Bladder), [1.80%, 0.48%](Body), [3.87%, 1.79%](L Femoral Head), [5.07%, 2.55%](R Femoral Head), and [1.26%, 1.62%](Rectum) of the prescription dose. We thus managed to map a desired radiation dose distribution from a patient’s PTV and OAR contours. As an additional advantage, relatively little data was used in the techniques and models described in this paper.

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A −/− , CPT2 −/− , ACAD9 −/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy. Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.

In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer. Neck dissection and/or elective nodal irradiation (ENI) are commonly performed in patients with head and neck squamous cell carcinoma (HNSCC) to minimize local and regional recurrence. However, here the authors show that ENI blunts the immune response to combined radiation and immunotherapy, increasing local and distant tumor growth in HNSCC preclinical models.